# Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed hiPSCs to Differentiated Neuronal and Cardiac Progeny

Authors: Leonhard Linta; Marianne Stockmann; Qiong Lin; André Lechel; Christian Proepper; Tobias M. Boeckers; Alexander Kleger; Stefan Liebau
Journal: Stem Cells International
 (2013)

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## Abstract

Ion channels are involved in a large variety of cellular processes including stem cell differentiation. Numerous families of ion channels are present in the organism which can be distinguished by means of, for example, ion selectivity, gating mechanism, composition, or cell biological function. To characterize the distinct expression of this group of ion channels we have compared the mRNA expression levels of ion channel genes between human keratinocyte-derived induced pluripotent stem cells (hiPSCs) and their somatic cell source, keratinocytes from plucked human hair. This comparison revealed that 26% of the analyzed probes showed an upregulation of ion channels in hiPSCs while just 6% were downregulated. Additionally, iPSCs express a much higher number of ion channels compared to keratinocytes. Further, to narrow down specificity of ion channel expression in iPS cells we compared their expression patterns with differentiated progeny, namely, neurons and cardiomyocytes derived from iPS cells. To conclude, hiPSCs exhibit a very considerable and diverse ion channel expression pattern. Their detailed analysis could give an insight into their contribution to many cellular processes and even disease mechanisms.


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## Body

## 1. Introduction

Ion channels are comprised of a large variety of differing families of pore proteins. Initially, ion channels were mostly known for their role in the nervous system where they play a crucial role in the signal transmission over neurites and synapses. But in fact they are involved in numerous other cellular processes including cell size regulation, muscle contractions, immune system activation [1], or hormone release [2]. Distinct ion channels are furthermore recognized to be of high importance for excitable cells of the heart: cardiomyocytes of the working myocardium as well as cells of the cardiac conduction system. In the heart, specific ion channels are responsible, for example, for the regulated generation of action potentials and for cardiac muscle contraction strength and time [3]. Additionally, ion channels play an important role in several differentiation and maturation processes [4–6]. The presented study aims to take a closer look at ion channel expression in human-induced pluripotent stem cells (hiPSCs) to give a start point for further analyses of their distinct roles at an early developmental cell state and differentiation processes.hiPSCs are generated from somatic cells by timed overexpression of specific transcription factors and strongly resemble pluripotent embryonic stem cells [7, 8]. Pluripotency is amongst others defined by the ability to differentiate into cells of all three germ layers and unlimited symmetrical cell division. This cell system is widely utilized for studies investigating developmental processes or disease mechanisms [9, 10]. Although it has become clear that differentiation processes influence ion channel expression [11], the distinct role of ion channels during these processes is so far only poorly understood. Nevertheless, it became evident that certain ion channels play a pivotal role in stem cell biology, including cell fate determination, cell cycle regulation, or cytoskeletal reorganization [6, 12–15].The possibilities of iPSCs include the generation of individual or patient-specific-pluripotent cells, which can be subsequently differentiated into the affected cell types. This is already utilized to study pathomechanisms in a variety of tissues and cell types [9, 16–18]. The so-called channelopathies which are based on mutations in ion channels are the cause of developmental disorders and are the subject of various studies [19, 20]. To elucidate the role of ion channels in cell differentiation, maturation or their role in pathomechanisms a well-founded knowledge of ion channel distribution in pluripotent cells, representing one of the earliest stages of development, is indispensable. In that respect, we compared the expression levels of several ion channels in human keratinocytes with their reprogrammed progeny, hiPSCs. Keratinocytes derived from plucked human hair [21, 22] represent one of the most promising cell sources for the generation of the investigated hiPSCs [23]. We have elucidated ion channel regulation for various channel families and their subtypes. Additionally, we compared the expression levels of ion channel families and subtypes, found to be regulated during reprogramming, with iPSC-differentiated progeny, namely, neurons and cardiomyocytes. These comparisons could be a start point to evaluate the contribution and function of different ion channels, for example, for self-renewal and differentiation processes in stem cells.


## 2. Material and Methods

### 2.1. Ethical Statement and Donor Information

After informed consent was given by the donors (ethical agreement by the University of Ulm, number 88/12) hair with intact hair roots was gathered by plucking from the scalp after desinfection. We used hair from healthy volunteers (age between 24 to 45 and both male and female gender).


### 2.2. hiPSC Generation and Cell Culture

Keratinocytes were obtained from plucked human scalp hair as already described [22]. Keratinocytes were propagated in EpiLife medium with HKGS supplement (both Invitrogen, Carlsbad, CA, USA). hiPSCs were generated from keratinocytes by lentiviral transduction of four reprogramming factors (Oct4, Sox2, Klf4, and cMyc) as described earlier [23]. After the reprogramming on rat embryonic fibroblasts they were maintained feeder-free on Matrigel (BD Biosciences, Franklin Lakes, NJ, USA) coated dishes in mTeSR1 medium (Stemcell Technologies, Vancouver, CA, USA).


### 2.3. Gene Expression Microarrays

Gene expression microarrays were performed for 6 keratinocyte samples and 9 hiPSC samples with the Agilent Whole Human Genome Microarray Kit (4x44k microarray kit G4112F, Agilent Technologies, Santa Clara, CA, USA). 500 ng of total RNA was used to produce Cy3-CTP-labeled cRNA with the Agilent Low RNA Input Liner Amplification Kit. The cRNA was purified and 1,65μg per array was hybridized for 17 h at 65°C and 10 r.p.m. Afterwards, the arrays were washed with Agilent Gene Expression Wash Buffers one and two and finally with acetonitrile for 1 min. The slides were scanned using Scan Control 7.0 software with a resolution of 5 μm. Scan data was extracted with the Feature Extraction 9.1 software. Expression levels were background adjusted and quantile normalized with the GeneSpring GX 12 software. Differential expression between keratinocytes and hiPSCs was analyzed using student’s t-test. A fold change > 2 and a P value < 0.05 was considered significant and highlighted bold (upregulation) or italic (downregulation) in the results table. For comparisons of iPSCs with iPSC-derived neurons published data from GSE34879 (GSM856936, GSM856937, GSM856915, GSM856916) and for cardiomyocytes GSE17579 (GSM438022, GSM438026, GSM438034, GSM438021, GSM438032, GSM438036) were used (both from NCBI Gene Expression Omnibus, http://www.ncbi.nlm.nih.gov/geo/). Fold change is shown if  >2.


## 2.1. Ethical Statement and Donor Information

After informed consent was given by the donors (ethical agreement by the University of Ulm, number 88/12) hair with intact hair roots was gathered by plucking from the scalp after desinfection. We used hair from healthy volunteers (age between 24 to 45 and both male and female gender).


## 2.2. hiPSC Generation and Cell Culture

Keratinocytes were obtained from plucked human scalp hair as already described [22]. Keratinocytes were propagated in EpiLife medium with HKGS supplement (both Invitrogen, Carlsbad, CA, USA). hiPSCs were generated from keratinocytes by lentiviral transduction of four reprogramming factors (Oct4, Sox2, Klf4, and cMyc) as described earlier [23]. After the reprogramming on rat embryonic fibroblasts they were maintained feeder-free on Matrigel (BD Biosciences, Franklin Lakes, NJ, USA) coated dishes in mTeSR1 medium (Stemcell Technologies, Vancouver, CA, USA).


## 2.3. Gene Expression Microarrays

Gene expression microarrays were performed for 6 keratinocyte samples and 9 hiPSC samples with the Agilent Whole Human Genome Microarray Kit (4x44k microarray kit G4112F, Agilent Technologies, Santa Clara, CA, USA). 500 ng of total RNA was used to produce Cy3-CTP-labeled cRNA with the Agilent Low RNA Input Liner Amplification Kit. The cRNA was purified and 1,65μg per array was hybridized for 17 h at 65°C and 10 r.p.m. Afterwards, the arrays were washed with Agilent Gene Expression Wash Buffers one and two and finally with acetonitrile for 1 min. The slides were scanned using Scan Control 7.0 software with a resolution of 5 μm. Scan data was extracted with the Feature Extraction 9.1 software. Expression levels were background adjusted and quantile normalized with the GeneSpring GX 12 software. Differential expression between keratinocytes and hiPSCs was analyzed using student’s t-test. A fold change > 2 and a P value < 0.05 was considered significant and highlighted bold (upregulation) or italic (downregulation) in the results table. For comparisons of iPSCs with iPSC-derived neurons published data from GSE34879 (GSM856936, GSM856937, GSM856915, GSM856916) and for cardiomyocytes GSE17579 (GSM438022, GSM438026, GSM438034, GSM438021, GSM438032, GSM438036) were used (both from NCBI Gene Expression Omnibus, http://www.ncbi.nlm.nih.gov/geo/). Fold change is shown if  >2.


## 3. Results

### 3.1. Differential Expression of Ion Channels in hiPSCs Compared to Keratinocytes

We first compared the expression of various ion channel families from keratinocytes to hiPSCs and from hiPSCs to cardiomyocytes and neurons, respectively. From the 387 probes (Table1) binding in ion channel genes from parental keratinocytes to hiPSCs, 101 (26%) showed a significant increase in expression (fold change > 2, P<0.05; labeled in bold) while 23 (6%) showed a significant decrease (fold change > −2, P<0.05; labeled in italic). In a second step differentially regulated ion channels from hiPSCs to hiPSC-derived neurons were investigated and we found 29 ion channel transcripts to be upregulated (fold change > 2; labeled in bold) while 6 showed a significant decrease (fold change > −2; labeled in italic). For cardiomyocytes, mRNA levels of only 7 ion channel members were upregulated (fold change > 2; labeled in bold) and 10 mRNA levels showed a significant decrease (fold change > −2; labeled in italic).Table 1
The expression levels for ion channel genes were compared in hiPSCs (9 samples) and keratinocytes (6 samples) via microarray. Gene names, accession numbers, and gene symbols are shown together with the corresponding fold change andP values. Significant changes (defined as fold change > 2, P<0.05) are labeled in bold for upregulation or italic for downregulation. Accession numbers refer to the NCBI or Ensembl (numbers starting with ENST) databases. Analyses of hiPSC-derived neurons or hiPSC-derived cardiomyocytes were performed using published data sets from GSE34879 (neurons) and GSE17579 (cardiomyocytes). These data sets already contain both iPSCs and differentiated progeny. Fold changes > 2 (marked bold) and <−2 (marked italic) are shown in the respective columns.
(a)
Voltage-gated calcium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Calcium channel, voltage-dependent, P/Q type, alpha 1A subunit, transcript variant 1
NM_000068
CACNA1A
2.26
E
-
01
−1.32
Calcium channel, voltage-dependent, N type, alpha 1B subunit
NM_000718
CACNA1B
7.27
E
-
01
−1.10
Calcium channel, voltage-dependent, N type, alpha 1B subunit [Source: HGNC Symbol; Acc: 1389]
ENST00000277550
CACNA1B
7.15
E
-
01
−1.14
Calcium channel, voltage-dependent, N type, alpha 1B subunit
NM_000718
CACNA1B
6.32
E
-
09
6.82
Calcium channel, voltage-dependent, N type, alpha 1B subunit [Source: HGNC Symbol; Acc: 1389]
ENST00000277551
CACNA1B
3.32
E
-
02
−1.57
Calcium channel, voltage-dependent, L type, alpha 1C subunit, transcript variant 18
NM_000719
CACNA1C
6.77
E
-
02
−1.37
Calcium channel, voltage-dependent, L type, alpha 1C subunit, transcript variant 18
NM_000719
CACNA1C
5.72
E
-
03
2.37
2.94
Calcium channel, voltage-dependent, L type, alpha 1D subunit, transcript variant 1
NM_000720
CACNA1D
3.83
E
-
01
1.58
Calcium channel, voltage-dependent, R type, alpha 1E subunit, transcript variant 3
NM_000721
CACNA1E
3.10
E
-
02
−4.48
2.08
Calcium channel, voltage-dependent, R type, alpha 1E subunit [Source: HGNC Symbol; Acc: 1392]
ENST00000524607
CACNA1E
8.83
E
-
01
1.05
Calcium channel, voltage-dependent, L type, alpha 1F subunit
NM_005183
CACNA1F
8.92
E
-
01
1.02
Calcium channel, voltage-dependent, T type, alpha 1G subunit, transcript variant 15
NM_198397
CACNA1G
6.42
E
-
01
−1.12
4.60
Calcium channel, voltage-dependent, T type, alpha 1G subunit, transcript variant 1
NM_018896
CACNA1G
5.37
E
-
07
6.96
Calcium channel, voltage-dependent, T type, alpha 1H subunit, transcript variant 1
NM_021098
CACNA1H
7.38
E
-
10
6.78
Calcium channel, voltage-dependent, T type, alpha 1I subunit, transcript variant 1
NM_021096
CACNA1I
2.22
E
-
11
37.25
Calcium channel, voltage-dependent, T type, alpha 1I subunit, transcript variant 1
NM_021096
CACNA1I
7.56
E
-
02
−1.56
Calcium channel, voltage-dependent, L type, alpha 1S subunit
NM_000069
CACNA1S
5.22
E
-
02
−1.97
Calcium channel, voltage-dependent, alpha 2/delta subunit 1
NM_000722
CACNA2D1
1.38
E
-
09
9.65
Calcium channel, voltage-dependent, alpha 2/delta subunit 2, transcript variant 1
NM_001005505
CACNA2D2
3.30
E
-
10
62.50
2.02
Calcium channel, voltage-dependent, alpha 2/delta subunit 3
NM_018398
CACNA2D3
5.14
E
-
05
5.42
2.55
Calcium channel, voltage-dependent, alpha 2/delta subunit 3
AF516696
CACNA2D3
4.68
E
-
11
33.67
Calcium channel, voltage-dependent, alpha 2/delta subunit 4
NM_172364
CACNA2D4
2.95
E
-
01
−1.41
Calcium channel, voltage-dependent, beta 1 subunit, transcript variant 3
NM_199248
CACNB1
4.31
E
-
01
−1.14
Calcium channel, voltage-dependent, beta 1 subunit, transcript variant 1
NM_000723
CACNB1
8.02
E
-
01
−1.02
Calcium channel, voltage-dependent, beta 1 subunit, transcript variant 1
NM_000723
CACNB1
6.22
E
-
01
1.04
cDNA FLJ45229 fis, clone BRCAN2020972,
AK128769
CACNB2
9.78
E
-
01
1.02
Calcium channel, voltage-dependent, beta 2 subunit, transcript variant 1
NM_000724
CACNB2
4.71
E
-
02
3.45
Calcium channel, voltage-dependent, beta 3 subunit, transcript variant 1
NM_000725
CACNB3
3.55
E
-
02
−1.93
9.56
Calcium channel, voltage-dependent, beta 3 subunit, transcript variant 1
NM_000725
CACNB3
6.61
E
-
01
1.09
Calcium channel, voltage-dependent, beta 4 subunit, transcript variant 1
NM_001005747
CACNB4
1.33
E
-
03
4.43
Calcium channel, voltage-dependent, gamma subunit 1
NM_000727
CACNG1
9.46
E
-
01
1.02
Calcium channel, voltage-dependent, gamma subunit 2
NM_006078
CACNG2
4.19
E
-
01
−1.29
Calcium channel, voltage-dependent, gamma subunit 2
NM_006078
CACNG2
7.91
E
-
01
1.09
Calcium channel, voltage-dependent, gamma subunit 3
NM_006539
CACNG3
2.21
E
-
01
−1.95
Calcium channel, voltage-dependent, gamma subunit 4
NM_014405
CACNG4
4.93
E
-
01
1.14
Calcium channel, voltage-dependent, gamma subunit 5
NM_145811
CACNG5
7.49
E
-
01
−1.13
Calcium channel, voltage-dependent, gamma subunit 5 [Source: HGNC Symbol; Acc: 1409]
ENST00000169565
CACNG5
2.19
E
-
01
−1.56
Calcium channel, voltage-dependent, gamma subunit 6, transcript variant 1
NM_145814
CACNG6
5.56
E
-
11
46.40
Calcium channel, voltage-dependent, gamma subunit 7
NM_031896
CACNG7
3.54
E
-
13
1439.36
3.37
Calcium channel, voltage-dependent, gamma subunit 7
NM_031896
CACNG7
1.82
E
-
01
1.26
Calcium channel, voltage-dependent, gamma subunit 8
NM_031895
CACNG8
2.01
E
-
01
1.43
Calcium channel, voltage-dependent, gamma subunit 8
NM_031895
CACNG8
1.18
E
-
09
9.70
(b)
Sperm-associated cation channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Cation channel, sperm associated 1
NM_053054
CATSPER1
3.26
E
-
01
1.51
Cation channel, sperm associated 2, transcript variant 2
NM_172095
CATSPER2
1.32
E
-
04
−2.78
Cation channel, sperm associated 2, transcript variant 4
NM_172097
CATSPER2
3.12
E
-
02
−1.78
Cation channel, sperm associated 3
NM_178019
CATSPER3
1.50
E
-
03
1.93
Cation channel, sperm associated 4
NM_198137
CATSPER4
2.51
E
-
01
1.48
Cation channel, sperm-associated, beta
NM_024764
CATSPERB
4.38
E
-
01
−1.25
Cation channel, sperm-associated, gamma
NM_021185
CATSPERG
3.56
E
-
01
1.34
(c)
Nicotinic acetylcholine receptors
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Cholinergic receptor, nicotinic, alpha 1 (muscle), transcript variant 1
NM_001039523
CHRNA1
8.06
E
-
01
−1.10
Cholinergic receptor, nicotinic, alpha 1 (muscle),  (cDNA clone IMAGE: 4124038), with apparent retained intron
BC006314
CHRNA1
4.64
E
-
01
1.47
Cholinergic receptor, nicotinic, alpha 2 (neuronal)
NM_000742
CHRNA2
6.05
E
-
01
−1.30
Cholinergic receptor, nicotinic, alpha 3, transcript variant 1
NM_000743
CHRNA3
1.84
E
-
10
34.22
Cholinergic receptor, nicotinic, alpha 4
NM_000744
CHRNA4
6.79
E
-
01
1.15
Cholinergic receptor, nicotinic, alpha 4 (neuronal), exon 1
X89741
CHRNA4
2.79
E
-
02
−2.53
Cholinergic receptor, nicotinic, alpha 5
NM_000745
CHRNA5
4.03
E
-
05
3.41
Cholinergic receptor, nicotinic, alpha 6, transcript variant 1
NM_004198
CHRNA6
2.23
E
-
01
−1.27
2.21
Cholinergic receptor, nicotinic, alpha 7, transcript variant 1
NM_000746
CHRNA7
4.61
E
-
04
1.86
Cholinergic receptor, nicotinic, alpha 7, transcript variant 2
NM_001190455
CHRNA7
1.56
E
-
11
13.24
Cholinergic receptor, nicotinic, alpha 9
NM_017581
CHRNA9
6.30
E
-
06
6.15
Cholinergic receptor, nicotinic, alpha 10
NM_020402
CHRNA10
1.57
E
-
02
1.57
Cholinergic receptor, nicotinic, beta 1 (muscle)
NM_000747
CHRNB1
8.07
E
-
04
−2.47
Cholinergic receptor, nicotinic, beta 1 (muscle)
NM_000747
CHRNB1
8.87
E
-
03
−1.92
Cholinergic receptor, nicotinic, beta 2 (neuronal)
NM_000748
CHRNB2
6.03
E
-
04
−3.01
Cholinergic receptor, nicotinic, beta 2 (neuronal) [Source: HGNC Symbol; Acc: 1962]
ENST00000368476
CHRNB2
2.98
E
-
09
32.05
Cholinergic receptor, nicotinic, beta 3
NM_000749
CHRNB3
5.91
E
-
01
1.12
Cholinergic receptor, nicotinic, beta 4
NM_000750
CHRNB4
1.76
E
-
02
4.20
Cholinergic receptor, nicotinic, delta
NM_000751
CHRND
9.84
E
-
01
1.01
Cholinergic receptor, nicotinic, epsilon
NM_000080
CHRNE
3.66
E
-
01
−1.20
Cholinergic receptor, nicotinic, gamma
NM_005199
CHRNG
6.70
E
-
01
1.14
(d)
Cyclic nucleotide-gated channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Cyclic nucleotide-gated channel alpha 1, transcript variant 2
NM_000087
CNGA1
7.14
E
-
01
1.15
Cyclic nucleotide-gated channel alpha 1, transcript variant 2
NM_000087
CNGA1
1.18
E
-
02
2.00
Cyclic nucleotide-gated channel alpha 3, transcript variant 1
NM_001298
CNGA3
2.00
E
-
01
1.21
Cyclic nucleotide-gated channel alpha 4
NM_001037329
CNGA4
2.78
E
-
01
1.82
Cyclic nucleotide-gated channel beta 1, transcript variant 1
NM_001297
CNGB1
9.22
E
-
03
−2.05
Cyclic nucleotide-gated channel beta 1, transcript variant 1
NM_001297
CNGB1
6.36
E
-
01
-
1.13
Cyclic nucleotide-gated channel beta 3
NM_019098
CNGB3
2.93
E
-
01
1.78
(e)
GABA receptors
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Gamma-aminobutyric acid (GABA) A receptor, alpha 1, transcript variant 1
NM_000806
GABRA1
1.26
E
-
01
1.41
Gamma-aminobutyric acid (GABA) A receptor, alpha 1, transcript variant 1
NM_000806
GABRA1
8.87
E
-
01
1.05
Gamma-aminobutyric acid (GABA) A receptor, alpha 2, transcript variant 1
NM_000807
GABRA2
9.70
E
-
02
1.70
Gamma-aminobutyric acid (GABA) A receptor, alpha 2, transcript variant 1
NM_000807
GABRA2
4.49
E
-
01
1.48
Gamma-aminobutyric acid (GABA) A receptor, alpha 3
NM_000808
GABRA3
2.10
E
-
01
1.43
Gamma-aminobutyric acid (GABA) A receptor, alpha 4, transcript variant 1
NM_000809
GABRA4
3.76
E
-
01
1.43
Gamma-aminobutyric acid (GABA) A receptor, alpha 4, transcript variant 1
NM_000809
GABRA4
8.30
E
-
01
1.05
Gamma-aminobutyric acid (GABA) A receptor, alpha 5, transcript variant 1
NM_000810
GABRA5
1.09
E
-
08
14.41
Gamma-aminobutyric acid (GABA) A receptor, alpha 6
NM_000811
GABRA6
1.69
E
-
01
1.23
Gamma-aminobutyric acid (GABA) A receptor, beta 1
NM_000812
GABRB1
1.14
E
-
01
1.43
Gamma-aminobutyric acid (GABA) A receptor, beta 2, transcript variant 2
NM_000813
GABRB2
1.27
E
-
02
1.94
Gamma-aminobutyric acid (GABA) A receptor, beta 3, transcript variant 1
NM_000814
GABRB3
6.70
E
-
10
85.93
−4.49
Gamma-aminobutyric acid (GABA) A receptor, beta 3, transcript variant 1
NM_000814
GABRB3
1.15
E
-
09
115.69
Gamma-aminobutyric acid (GABA) A receptor, delta
NM_000815
GABRD
6.26
E
-
02
3.02
Gamma-aminobutyric acid (GABA) A receptor, epsilon
NM_004961
GABRE
5.83
E
-
05
−5.47
Gamma-aminobutyric acid (GABA) A receptor, Gamma 1
NM_173536
GABRG1
1.78
E
-
01
1.24
Gamma-aminobutyric acid (GABA) A receptor, Gamma 1
NM_173536
GABRG1
1.70
E
-
02
2.19
Gamma-aminobutyric acid (GABA) A receptor, Gamma 2, transcript variant 1
NM_198904
GABRG2
6.02
E
-
01
1.14
Gamma-aminobutyric acid (GABA) A receptor, Gamma 2, transcript variant 2
NM_000816
GABRG2
5.28
E
-
02
1.72
Gamma-aminobutyric acid (GABA) A receptor, Gamma 2, transcript variant 2
NM_000816
GABRG2
9.47
E
-
09
8.41
Gamma-aminobutyric acid (GABA) A receptor, Gamma 3
NM_033223
GABRG3
1.99
E
-
01
2.00
Gamma-aminobutyric acid (GABA) A receptor, Gamma 3
NM_033223
GABRG3
1.04
E
-
01
1.61
Gamma-aminobutyric acid (GABA) A receptor, pi
NM_014211
GABRP
6.62
E
-
01
−1.12
17.25
Gamma-aminobutyric acid (GABA) receptor, theta
NM_018558
GABRQ
1.60
E
-
01
1.56
Gamma-aminobutyric acid (GABA) receptor, theta
NM_018558
GABRQ
4.76
E
-
01
−1.27
Gamma-aminobutyric acid (GABA) receptor, theta [Source: HGNC Symbol; Acc: 14454]
ENST00000370306
GABRQ
8.22
E
-
09
52.17
Gamma-aminobutyric acid (GABA) receptor, rho 1
NM_002042
GABRR1
8.94
E
-
01
−1.04
Gamma-aminobutyric acid (GABA) receptor, rho 2
NM_002043
GABRR2
2.83
E
-
01
1.54
Gamma-aminobutyric acid (GABA) receptor, rho 3
NM_001105580
GABRR3
3.05
E
-
01
−1.34
(f)
Glycine receptors
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Glycine receptor, alpha 1, transcript variant 2
NM_000171
GLRA1
5.47
E
-
01
−1.29
Glycine receptor, alpha 2, transcript variant 1
NM_002063
GLRA2
1.17
E
-
01
1.42
11.41
Glycine receptor, alpha 3, transcript variant 1
NM_006529
GLRA3
5.16
E
-
01
−1.26
Glycine receptor, alpha 3 [Source: HGNC Symbol; Acc: 4328]
ENST00000274093
GLRA3
8.33
E
-
02
1.64
Glycine receptor, alpha 3, transcript variant 1
NM_006529
GLRA3
1.46
E
-
01
1.41
Glycine receptor, alpha 4, transcript variant 1
NM_001024452
GLRA4
7.75
E
-
01
1.17
Glycine receptor, beta, transcript variant 1
NM_000824
GLRB
6.38
E
-
02
−1.69
6.61
(g)
Ionotropic glutamate receptors
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Glutamate receptor, ionotropic, AMPA 1, transcript variant 1
NM_000827
GRIA1
7.65
E
-
01
−1.20
2.06
Glutamate receptor, ionotropic, AMPA 2, transcript variant 1
NM_000826
GRIA2
2.87
E
-
01
−1.87
21.26
Glutamate receptor, ionotropic, AMPA 2, transcript variant 1
NM_000826
GRIA2
2.72
E
-
01
1.33
Glutamate receptor, ionotropic, AMPA 2, transcript variant 1
NM_000826
GRIA2
6.54
E
-
01
1.22
Glutamate receptor, ionotropic, AMPA 3, transcript variant 2
NM_000828
GRIA3
5.05
E
-
01
1.26
Glutamate receptor, ionotropic, AMPA 3 [Source: HGNC Symbol; Acc: 4573]
ENST00000371264
GRIA3
1.14
E
-
01
1.50
Glutamate receptor, ionotropic, AMPA 3, transcript variant 2
NM_000828
GRIA3
9.05
E
-
01
−1.05
Glutamate receptor, ionotropic, AMPA 4, transcript variant 1
NM_000829
GRIA4
2.30
E
-
02
1.80
3.73
Glutamate receptor, ionotropic, delta 1
NM_017551
GRID1
1.82
E
-
01
1.50
Glutamate receptor, ionotropic, delta 1
NM_017551
GRID1
5.08
E
-
05
3.63
Glutamate receptor, ionotropic, delta 2
NM_001510
GRID2
7.64
E
-
01
−1.11
Glutamate receptor, ionotropic, delta 2
NM_001510
GRID2
5.55
E
-
09
55.66
Glutamate receptor, ionotropic, kainate 1, transcript variant 1
NM_000830
GRIK1
1.64
E
-
01
1.29
2.58
Glutamate receptor, ionotropic, kainate 2, transcript variant 3
NM_001166247
GRIK2
1.42
E
-
01
1.56
2.53
Glutamate receptor, ionotropic, kainate 2, transcript variant 1
NM_021956
GRIK2
1.14
E
-
01
−2.01
Glutamate receptor, ionotropic, kainate 2, transcript variant 2
NM_175768
GRIK2
7.80
E
-
01
1.08
Glutamate receptor, ionotropic, kainate 3
NM_000831
GRIK3
1.58
E
-
01
1.64
Glutamate receptor, ionotropic, kainate 3
NM_000831
GRIK3
6.15
E
-
10
22.64
Glutamate receptor, ionotropic, kainate 4 [Source: HGNC Symbol; Acc: 4582]
ENST00000527524
GRIK4
1.77
E
-
11
18.10
Glutamate receptor, ionotropic, kainate 4
NM_014619
GRIK4
5.73
E
-
02
2.54
Glutamate receptor, ionotropic, kainate 5
NM_002088
GRIK5
2.65
E
-
03
1.79
−2.41
Glutamate receptor, ionotropic, N-methyl D-aspartate 1, transcript variant NR1-3
NM_007327
GRIN1
1.93
E
-
02
−3.02
2.69
Glutamate receptor, ionotropic, N-methyl D-aspartate 1, transcript variant NR1-3
NM_007327
GRIN1
6.01
E
-
02
−2.45
Glutamate receptor, ionotropic, N-methyl D-aspartate 1, transcript variant NR1-3
NM_007327
GRIN1
3.86
E
-
01
−1.65
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A, transcript variant 2
NM_000833
GRIN2A
6.54
E
-
01
1.18
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A, transcript variant 2
NM_000833
GRIN2A
9.21
E
-
01
−1.02
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A, transcript variant 1
NM_001134407
GRIN2A
3.32
E
-
10
29.85
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A, transcript variant 2
NM_000833
GRIN2A
2.63
E
-
01
1.55
Glutamate receptor, ionotropic, N-methyl D-aspartate 2B
NM_000834
GRIN2B
6.64
E
-
01
−1.26
Glutamate receptor, ionotropic, N-methyl D-aspartate 2C
NM_000835
GRIN2C
8.01
E
-
01
−1.08
Glutamate receptor, ionotropic, N-methyl D-aspartate 2C
NM_000835
GRIN2C
5.01
E
-
01
1.13
Glutamate receptor, ionotropic, N-methyl D-aspartate 2D
NM_000836
GRIN2D
4.69
E
-
02
−1.82
Glutamate receptor, ionotropic, N-methyl-D-aspartate 3A
NM_133445
GRIN3A
3.28
E
-
01
−1.41
Glutamate receptor, ionotropic, N-methyl-D-aspartate 3B
NM_138690
GRIN3B
9.36
E
-
01
−1.02
Glutamate receptor, ionotropic, N-methyl D-aspartate-associated protein 1 (glutamate binding), transcript variant 1
NM_000837
GRINA
3.68
E
-
04
−2.05
2.05
NMDA receptor glutamate-binding chain (hnrgw), partial
U44954
GRINA
3.06
E
-
04
−1.81
(h)
Hyperpolarization-activated cyclic nucleotide-gated channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 1
NM_021072
HCN1
3.47
E
-
11
52.85
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 1
NM_021072
HCN1
1.01
E
-
08
9.91
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 2
NM_001194
HCN2
5.36
E
-
02
−1.63
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 3
NM_020897
HCN3
1.98
E
-
02
2.12
6.56
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 4
NM_005477
HCN4
1.01
E
-
01
−1.66
(i)
Serotonin receptors
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
5-hydroxytryptamine (serotonin) receptor 3A, transcript variant 1
NM_213621
HTR3A
1.99
E
-
03
2.77
−2.20
5-hydroxytryptamine (serotonin) receptor 3A, transcript variant 1
NM_213621
HTR3A
2.63
E
-
11
11.11
5-hydroxytryptamine (serotonin) receptor 3B
NM_006028
HTR3B
1.99
E
-
01
−1.54
5-hydroxytryptamine (serotonin) receptor 3, family member C
NM_130770
HTR3C
4.81
E
-
01
1.34
5-hydroxytryptamine (serotonin) receptor 3 family member D, transcript variant 2
NM_182537
HTR3D
4.75
E
-
01
−1.37
5-hydroxytryptamine (serotonin) receptor 3, family member E
NM_182589
HTR3E
1.52
E
-
01
−1.44
(j)
Voltage-gated potassium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Potassium voltage-gated channel, shaker-related subfamily, member 1 (episodic ataxia with myokymia)
NM_000217
KCNA1
1.64
E
-
01
2.00
Potassium voltage-gated channel, shaker-related subfamily, member 1 (episodic ataxia with myokymia)
NM_000217
KCNA1
1.31
E
-
01
1.87
Potassium voltage-gated channel, shaker-related subfamily, member 2, transcript variant 2
NM_001204269
KCNA2
8.55
E
-
02
1.33
Potassium voltage-gated channel, shaker-related subfamily, member 2, transcript variant 1
NM_004974
KCNA2
8.33
E
-
01
1.06
Potassium voltage-gated channel, shaker-related subfamily, member 3
NM_002232
KCNA3
2.43
E
-
01
1.76
Potassium voltage-gated channel, shaker-related subfamily, member 4
NM_002233
KCNA4
5.75
E
-
01
1.11
Potassium voltage-gated channel, shaker-related subfamily, member 5
NM_002234
KCNA5
1.76
E
-
04
4.11
5.63
Potassium voltage-gated channel, shaker-related subfamily, member 6
NM_002235
KCNA6
7.20
E
-
02
2.28
Potassium voltage-gated channel, shaker-related subfamily, member 7
NM_031886
KCNA7
8.53
E
-
03
3.67
Potassium voltage-gated channel, shaker-related subfamily, member 7
NM_031886
KCNA7
1.04
E
-
01
2.39
Potassium voltage-gated channel, shaker-related subfamily, member 10
NM_005549
KCNA10
3.32
E
-
01
−1.62
Potassium voltage-gated channel, shaker-related subfamily, beta member 1, transcript variant 2
NM_003471
KCNAB1
2.70
E
-
01
1.46
Potassium voltage-gated channel, shaker-related subfamily, beta member 1, transcript variant 2
NM_003471
KCNAB1
3.60
E
-
02
2.42
Potassium voltage-gated channel, shaker-related subfamily, beta member 1, transcript variant 2
NM_003471
KCNAB1
7.87
E
-
02
3.06
Potassium voltage-gated channel, shaker-related subfamily, beta member 2, transcript variant 1
NM_003636
KCNAB2
5.35
E
-
01
−1.35
Potassium voltage-gated channel, shaker-related subfamily, beta member 2, transcript variant 1
NM_003636
KCNAB2
2.20
E
-
01
1.26
Potassium voltage-gated channel, shaker-related subfamily, beta member 3 [Source: HGNC Symbol; Acc: 6230]
ENST00000303790
KCNAB3
8.14
E
-
02
1.62
Potassium voltage-gated channel, shaker-related subfamily, beta member 3
NM_004732
KCNAB3
3.66
E
-
01
1.35
Potassium voltage-gated channel, Shab-related subfamily, member 1
NM_004975
KCNB1
7.42
E
-
08
16.32
2.59
Potassium voltage-gated channel, Shab-related subfamily, member 2
NM_004770
KCNB2
1.54
E
-
05
4.58
Potassium voltage-gated channel, Shaw-related subfamily, member 1, transcript variant A
NM_001112741
KCNC1
1.47
E
-
01
1.75
Potassium voltage-gated channel, Shaw-related subfamily, member 1, transcript variant B
NM_004976
KCNC1
4.86
E
-
08
13.97
Potassium voltage-gated channel, Shaw-related subfamily, member 1, transcript variant A
NM_001112741
KCNC1
2.17
E
-
01
1.56
Potassium voltage-gated channel, Shaw-related subfamily, member 2, transcript variant 1
NM_139136
KCNC2
8.53
E
-
01
1.06
Potassium voltage-gated channel, Shaw-related subfamily, member 2, transcript variant 2
NM_139137
KCNC2
4.04
E
-
01
1.34
Potassium voltage-gated channel, Shaw-related subfamily, member 3
NM_004977
KCNC3
3.56
E
-
01
1.20
Potassium voltage-gated channel, Shaw-related subfamily, member 4, transcript variant 3
NM_001039574
KCNC4
7.70
E
-
02
−1.40
Potassium voltage-gated channel, Shal-related subfamily, member 1
NM_004979
KCND1
1.48
E
-
04
7.11
Potassium voltage-gated channel, Shal-related subfamily, member 2
NM_012281
KCND2
1.62
E
-
12
91.08
2.76
−2.57
Potassium voltage-gated channel, Shal-related subfamily, member 2
NM_012281
KCND2
2.76
E
-
09
21.83
Potassium voltage-gated channel, Shal-related subfamily, member 3 [Source: HGNC Symbol; Acc: 6239]
ENST00000369697
KCND3
5.36
E
-
01
−1.36
Potassium voltage-gated channel, Shal-related subfamily, member 3, transcript variant 1
NM_004980
KCND3
1.05
E
-
01
1.55
Potassium voltage-gated channel, Shal-related subfamily, member 3, transcript variant 1
NM_004980
KCND3
4.41
E
-
01
1.37
Potassium voltage-gated channel, Shal-related subfamily, member 3 [Source: HGNC Symbol; Acc: 6239]
ENST00000369697
KCND3
3.86
E
-
04
−1.84
Potassium voltage-gated channel, Isk-related family, member 1, transcript variant 2
NM_000219
KCNE1
3.53
E
-
01
−1.45
Potassium voltage-gated channel, Isk-related family, member 1, transcript variant 2
NM_000219
KCNE1
3.59
E
-
01
1.25
KCNE1-like
NM_012282
KCNE1L
1.34
E
-
08
4.44
−2.18
KCNE1-like
NM_012282
KCNE1L
1.11
E
-
08
3.65
KCNE1-like
NM_012282
KCNE1L
6.41
E
-
03
1.88
Potassium voltage-gated channel, Isk-related family, member 2
NM_172201
KCNE2
1.41
E
-
04
3.93
Potassium voltage-gated channel, Isk-related family, member 3
NM_005472
KCNE3
8.65
E
-
15
52.36
Potassium voltage-gated channel, Isk-related family, member 4
NM_080671
KCNE4
5.04
E
-
01
1.20
Potassium voltage-gated channel, subfamily F, member 1
NM_002236
KCNF1
2.25
E
-
05
6.48
2.84
Potassium voltage-gated channel, subfamily G, member 1
NM_002237
KCNG1
8.51
E
-
03
−1.82
Potassium voltage-gated channel, subfamily G, member 1
NM_002237
KCNG1
1.55
E
-
01
−1.65
Potassium voltage-gated channel, subfamily G, member 2
NM_012283
KCNG2
6.21
E
-
02
1.32
Potassium voltage-gated channel, subfamily G, member 3, transcript variant 1
NM_133329
KCNG3
3.74
E
-
11
58.95
−2.93
Potassium voltage-gated channel, subfamily G, member 4
NM_172347
KCNG4
3.36
E
-
03
−3.33
Potassium voltage-gated channel, subfamily G, member 4,  (cDNA clone IMAGE: 3028985)
BC008969
KCNG4
2.24
E
-
04
−3.29
Potassium voltage-gated channel, subfamily H (eag-related), member 1, transcript variant 1
NM_172362
KCNH1
8.05
E
-
01
−1.15
Potassium voltage-gated channel, subfamily H (eag-related), member 2, transcript variant 1
NM_000238
KCNH2
5.94
E
-
04
37.53
Potassium voltage-gated channel, subfamily H (eag-related), member 2, transcript variant 2
NM_172056
KCNH2
5.70
E
-
03
1.73
Potassium voltage-gated channel, subfamily H (eag-related), member 3
NM_012284
KCNH3
9.65
E
-
01
1.01
Potassium voltage-gated channel, subfamily H (eag-related), member 4
NM_012285
KCNH4
3.18
E
-
01
−1.24
Potassium voltage-gated channel, subfamily H (eag-related), member 5, transcript variant 2
NM_172376
KCNH5
3.04
E
-
03
2.96
Potassium voltage-gated channel, subfamily H (eag-related), member 5, transcript variant 1
NM_139318
KCNH5
5.41
E
-
01
1.47
Potassium voltage-gated channel, subfamily H (eag-related), member 6, transcript variant 2
NM_173092
KCNH6
2.93
E
-
02
3.04
cDNA FLJ33650 fis, clone BRAMY2024514, highly similar to Rattus norvegicus Potassium channel (erg2)
AK090969
KCNH6
2.08
E
-
05
12.42
Potassium voltage-gated channel, subfamily H (eag-related), member 6, transcript variant 2
NM_173092
KCNH6
2.55
E
-
02
2.29
Potassium voltage-gated channel, subfamily H (eag-related), member 7, transcript variant 2
NM_173162
KCNH7
4.63
E
-
01
−1.40
Potassium voltage-gated channel, subfamily H (eag-related), member 7, transcript variant 1
NM_033272
KCNH7
7.58
E
-
01
−1.09
Potassium voltage-gated channel, subfamily H (eag-related), member 8
NM_144633
KCNH8
3.00
E
-
09
24.57
2.97
Kv channel interacting protein 1, transcript variant 1
NM_001034837
KCNIP1
8.33
E
-
02
1.96
4.24
Kv channel interacting protein 2, transcript variant 7
NM_173197
KCNIP2
6.43
E
-
01
1.21
Kv channel interacting protein 2, transcript variant 1
NM_014591
KCNIP2
2.53
E
-
03
1.96
Kv channel interacting protein 3, calsenilin, transcript variant 1
NM_013434
KCNIP3
1.15
E
-
03
−3.47
Kv channel interacting protein 4, transcript variant 5
NM_001035003
KCNIP4
6.73
E
-
01
1.16
2.01
Kv channel interacting protein 4, transcript variant 5
NM_001035003
KCNIP4
9.26
E
-
01
1.05
Potassium voltage-gated channel, KQT-like subfamily, member 1, transcript variant 1
NM_000218
KCNQ1
3.31
E
-
09
79.52
Potassium voltage-gated channel, KQT-like subfamily, member 2, transcript variant 5
NM_172109
KCNQ2
5.68
E
-
19
3408.43
Potassium voltage-gated channel, KQT-like subfamily, member 2, transcript variant 3
NM_004518
KCNQ2
1.29
E
-
02
1.82
Potassium voltage-gated channel, KQT-like subfamily, member 2,  (cDNA clone IMAGE: 4154700)
BC020384
KCNQ2
1.09
E
-
08
37.12
Potassium voltage-gated channel, KQT-like subfamily, member 3, transcript variant 1
NM_004519
KCNQ3
1.10
E
-
04
−1.69
Potassium voltage-gated channel, KQT-like subfamily, member 4, transcript variant 1
NM_004700
KCNQ4
9.77
E
-
01
1.02
Potassium voltage-gated channel, KQT-like subfamily, member 5, transcript variant 1
NM_019842
KCNQ5
9.81
E
-
02
−1.79
Potassium voltage-gated channel, delayed-rectifier, subfamily S, member 1
NM_002251
KCNS1
3.39
E
-
01
−1.27
−2.64
Potassium voltage-gated channel, delayed-rectifier, subfamily S, member 2
NM_020697
KCNS2
6.19
E
-
02
−2.45
2.11
Potassium voltage-gated channel, delayed-rectifier, subfamily S, member 3
NM_002252
KCNS3
1.04
E
-
04
2.22
−2.61
−2.39
Potassium channel, subfamily T, member 1 (sodium activated)
NM_020822
KCNT1
8.51
E
-
02
−2.17
Potassium channel, subfamily V, member 1
NM_014379
KCNV1
7.84
E
-
02
1.58
Potassium channel, subfamily V, member 2
NM_133497
KCNV2
7.63
E
-
01
−1.16
(k)
Inwardly rectifying potassium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Potassium inwardly-rectifying channel, subfamily J, member 1, transcript variant rom-k5
NM_153767
KCNJ1
2.54
E
-
02
2.66
Potassium inwardly-rectifying channel, subfamily J, member 1, transcript variant rom-k5
NM_153767
KCNJ1
8.51
E
-
01
−1.05
Potassium inwardly-rectifying channel, subfamily J, member 2
NM_000891
KCNJ2
5.14
E
-
04
4.38
Potassium inwardly-rectifying channel, subfamily J, member 3
NM_002239
KCNJ3
4.56
E
-
01
1.34
Potassium inwardly-rectifying channel, subfamily J, member 4, transcript variant 1
NM_152868
KCNJ4
4.80
E
-
02
2.30
Potassium inwardly-rectifying channel, subfamily J, member 5
NM_000890
KCNJ5
1.88
E
-
08
−45.40
Potassium inwardly-rectifying channel, subfamily J, member 5
NM_000890
KCNJ5
4.42
E
-
12
−109.11
Potassium inwardly-rectifying channel, subfamily J, member 6
NM_002240
KCNJ6
3.29
E
-
05
6.75
5.54
Potassium inwardly-rectifying channel, subfamily J, member 8
NM_004982
KCNJ8
1.98
E
-
04
5.97
2.74
Potassium inwardly-rectifying channel, subfamily J, member 9 [Source: HGNC Symbol; Acc: 6270]
ENST00000368088
KCNJ9
3.17
E
-
01
1.49
Potassium inwardly-rectifying channel, subfamily J, member 9
NM_004983
KCNJ9
3.07
E
-
01
1.79
Potassium inwardly-rectifying channel, subfamily J, member 10
NM_002241
KCNJ10
8.85
E
-
04
4.14
Potassium inwardly-rectifying channel, subfamily J, member 10
NM_002241
KCNJ10
9.56
E
-
01
1.01
Potassium inwardly-rectifying channel, subfamily J, member 11, transcript variant 1
NM_000525
KCNJ11
4.00
E
-
04
2.93
Potassium inwardly-rectifying channel, subfamily J, member 12
NM_021012
KCNJ12
1.00
E
-
01
1.47
Potassium inwardly-rectifying channel, subfamily J, member 12
NM_021012
KCNJ12
3.53
E
-
06
5.81
Potassium inwardly-rectifying channel, subfamily J, member 13, transcript variant 1
NM_002242
KCNJ13
7.75
E
-
01
1.20
Potassium inwardly-rectifying channel, subfamily J, member 14, transcript variant 2
NM_170720
KCNJ14
9.05
E
-
02
−1.40
Potassium inwardly-rectifying channel, subfamily J, member 15, transcript variant 1
NM_170736
KCNJ15
3.41
E
-
08
−150.95
Potassium inwardly-rectifying channel, subfamily J, member 16, transcript variant 2
NM_170741
KCNJ16
2.22
E
-
01
−1.93
(l)
Two-P potassium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Potassium channel, subfamily K, member 1
NM_002245
KCNK1
3.02
E
-
04
−1.68
Potassium channel, subfamily K, member 2, transcript variant 1
NM_001017424
KCNK2
3.46
E
-
01
1.57
Potassium channel, subfamily K, member 3
NM_002246
KCNK3
9.98
E
-
01
1.00
2.36
Potassium channel, subfamily K, member 3
NM_002246
KCNK3
8.75
E
-
01
−1.10
Potassium channel, subfamily K, member 3
NM_002246
KCNK3
5.34
E
-
01
−1.30
Potassium channel, subfamily K, member 3 [Source: HGNC Symbol; Acc: 6278]
ENST00000302909
KCNK3
2.53
E
-
01
1.52
Potassium channel, subfamily K, member 4
NM_033310
KCNK4
6.21
E
-
01
−1.14
2.05
Potassium channel, subfamily K, member 5
NM_003740
KCNK5
1.16
E
-
14
29.46
−2.35
−2.03
Potassium channel, subfamily K, member 6
NM_004823
KCNK6
1.22
E
-
06
−3.48
−2.20
Potassium channel, subfamily K, member 6
NM_004823
KCNK6
2.05
E
-
08
−5.11
Potassium channel, subfamily K, member 6
NM_004823
KCNK6
7.04E−06
−5.22
Potassium channel, subfamily K, member 7, transcript variant A
NM_033347
KCNK7
1.17
E
-
01
−1.52
Potassium channel, subfamily K, member 9
NM_016601
KCNK9
6.67
E
-
01
−1.29
Potassium channel, subfamily K, member 10, transcript variant 1
NM_021161
KCNK10
2.63
E
-
01
−1.30
Potassium channel, subfamily K, member 10, transcript variant 2
NM_138317
KCNK10
1.41
E
-
02
1.43
Potassium channel, subfamily K, member 12
NM_022055
KCNK12
4.58
E
-
10
23.40
−5.58
Potassium channel, subfamily K, member 13
NM_022054
KCNK13
7.65
E
-
01
−1.10
Potassium channel, subfamily K, member 15
NM_022358
KCNK15
4.96
E
-
02
−1.50
Potassium channel, subfamily K, member 15
NM_022358
KCNK15
9.10
E
-
01
−1.09
Pancreatic potassium channel TALK-1d;  alternatively spliced
AY253147
KCNK16
2.17
E
-
02
−2.43
Potassium channel, subfamily K, member 17, transcript variant 1
NM_031460
KCNK17
1.87
E
-
11
28.60
Potassium channel, subfamily K, member 17, transcript variant 1
NM_031460
KCNK17
1.52
E
-
05
19.62
Potassium channel, subfamily K, member 18
NM_181840
KCNK18
1.77
E
-
01
1.61
(m)
Calcium-activated potassium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 2
NM_002247
KCNMA1
1.01
E
-
02
1.84
2.01
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 1
NM_001014797
KCNMA1
3.19
E
-
01
1.32
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 2
NM_002247
KCNMA1
3.67
E
-
03
2.27
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 2
NM_002247
KCNMA1
8.53
E
-
02
1.44
Maxi-K channel HSLO
AF349445
KCNMA1
3.04
E
-
01
1.44
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 2
NM_002247
KCNMA1
2.15
E
-
01
−1.23
Potassium large conductance calcium-activated channel, subfamily M, beta member 1
NM_004137
KCNMB1
7.12
E
-
02
−1.41
Potassium large conductance calcium-activated channel, subfamily M, beta member 1
NM_004137
KCNMB1
2.23
E
-
06
7.82
Potassium large conductance calcium-activated channel, subfamily M, beta member 2, transcript variant 1
NM_181361
KCNMB2
3.36
E
-
01
1.56
Potassium large conductance calcium-activated channel, subfamily M, beta member 2, transcript variant 1
NM_181361
KCNMB2
1.17
E
-
01
1.47
Potassium large conductance calcium-activated channel, subfamily M beta member 3, transcript variant 1
NM_171828
KCNMB3
1.41
E
-
05
2.63
Potassium large conductance calcium-activated channel, subfamily M, beta member 4
NM_014505
KCNMB4
8.85
E
-
12
103.99
Potassium large conductance calcium-activated channel, subfamily M, beta member 4 [Source: HGNC Symbol; Acc: 6289]
ENST00000258111
KCNMB4
9.22
E
-
10
18.40
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 1
NM_002248
KCNN1
3.40
E
-
05
4.67
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2, transcript variant 1
NM_021614
KCNN2
1.88
E
-
13
22.23
−3.63
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3, transcript variant 1
NM_002249
KCNN3
2.58
E
-
06
8.25
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3, transcript variant 3
NM_001204087
KCNN3
1.11
E
-
07
15.29
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4
NM_002250
KCNN4
1.06
E
-
02
−1.84
(n)
P2X receptors
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Purinergic receptor P2X, ligand-gated ion channel, 1
NM_002558
P2RX1
7.71
E
-
01
1.14
Purinergic receptor P2X, ligand-gated ion channel, 2, transcript variant 4
NM_170683
P2RX2
5.25
E
-
02
−1.66
Purinergic receptor P2X, ligand-gated ion channel, 3
NM_002559
P2RX3
2.43
E
-
02
−1.76
Purinergic receptor P2X, ligand-gated ion channel, 4
NM_002560
P2RX4
8.68
E
-
01
−1.03
Purinergic receptor P2X, ligand-gated ion channel, 5, transcript variant 1
NM_002561
P2RX5
7.68
E
-
08
6.97
Purinergic receptor P2X, ligand-gated ion channel, 5, transcript variant 2
NM_175080
P2RX5
6.13
E
-
02
1.54
Purinergic receptor P2X, ligand-gated ion channel, 6 [Source: HGNC Symbol; Acc: 8538]
ENST00000413302
P2RX6
4.13
E
-
01
1.68
Purinergic receptor P2X, ligand-gated ion channel, 7, transcript variant 1
NM_002562
P2RX7
6.13
E
-
01
1.23
Purinergic receptor P2X, ligand-gated ion channel, 7, transcript variant 1
NM_002562
P2RX7
9.17
E
-
01
1.04
(o)
Transient receptor potential channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Polycystic kidney disease 2 (autosomal dominant)
NM_000297
PKD2
7.48
E
-
07
1.79
Polycystic kidney disease 2 (autosomal dominant)
NM_000297
PKD2
2.38
E
-
05
1.98
Polycystic kidney disease 2-like 1
NM_016112
PKD2L1
1.29
E
-
03
4.66
Polycystic kidney disease 2-like 2
NM_014386
PKD2L2
1.94
E
-
01
1.49
Polycystic kidney disease 2-like 2
NM_014386
PKD2L2
7.43
E
-
01
1.19
Polycystic kidney disease 2-like 2
NM_014386
PKD2L2
6.74
E
-
01
1.09
Transient receptor potential cation channel, subfamily A, member 1
NM_007332
TRPA1
2.99
E
-
01
1.74
Transient receptor potential cation channel, subfamily A, member 1
NM_007332
TRPA1
5.64
E
-
02
2.70
Transient receptor potential cation channel, subfamily C, member 1
NM_003304
TRPC1
4.30
E
-
06
2.01
Transient receptor potential cation channel, subfamily C, member 3, transcript variant 2
NM_003305
TRPC3
1.12
E
-
07
5.78
2.45
Transient receptor potential cation channel, subfamily C, member 4, transcript variant alpha
NM_016179
TRPC4
3.25
E
-
07
25.38
Transient receptor potential cation channel, subfamily C, member 5
NM_012471
TRPC5
1.20
E
-
01
1.28
Transient receptor potential cation channel, subfamily C, member 6
NM_004621
TRPC6
1.21
E
-
01
2.33
Transient receptor potential cation channel, subfamily C, member 7, transcript variant 1
NM_020389
TRPC7
6.18
E
-
01
−1.36
Transient receptor potential cation channel, subfamily M, member 1
NM_002420
TRPM1
2.29
E
-
01
1.31
Transient receptor potential cation channel, subfamily M, member 2, transcript variant 1
NM_003307
TRPM2
1.22
E
-
01
1.97
Transient receptor potential cation channel, subfamily M, member 2, transcript variant 1
NM_003307
TRPM2
5.04
E
-
02
2.53
Transient receptor potential cation channel, subfamily M, member 3, transcript variant 7
NM_206948
TRPM3
3.04
E
-
09
10.69
Transient receptor potential cation channel, subfamily M, member 3 [Source: HGNCSymbol; Acc: 17992]
ENST00000354500
TRPM3
2.34
E
-
03
3.74
Transient receptor potential cation channel, subfamily M, member 3, transcript variant 7
NM_206948
TRPM3
3.41
E
-
06
6.23
Transient receptor potential cation channel, subfamily M, member 3, transcript variant 9
NM_001007471
TRPM3
7.23
E
-
01
1.13
Transient receptor potential cation channel, subfamily M, member 3, transcript variant 9
NM_001007471
TRPM3
1.54
E
-
05
2.60
Transient receptor potential cation channel, subfamily M, member 4, transcript variant 1
NM_017636
TRPM4
3.72
E
-
02
−1.89
Transient receptor potential cation channel, subfamily M, member 5
NM_014555
TRPM5
8.21
E
-
01
−1.08
Transient receptor potential cation channel, subfamily M, member 6, transcript variant a
NM_017662
TRPM6
3.80
E
-
01
1.64
Transient receptor potential cation channel, subfamily M, member 6, transcript variant a
NM_017662
TRPM6
9.10
E
-
01
1.05
Transient receptor potential cation channel, subfamily M, member 6, transcript variant a
NM_017662
TRPM6
5.32
E
-
07
5.59
Transient receptor potential cation channel, subfamily M, member 6, transcript variant a
NM_017662
TRPM6
3.32
E
-
01
1.36
Transient receptor potential cation channel, subfamily M, member 7
NM_017672
TRPM7
2.16
E
-
02
−1.25
Transient receptor potential cation channel, subfamily M, member 7
NM_017672
TRPM7
3.64
E
-
03
−1.38
Transient receptor potential cation channel, subfamily M, member 8
NM_024080
TRPM8
2.04
E
-
01
1.89
Transient receptor potential cation channel, subfamily V, member 1, transcript variant 3
NM_080706
TRPV1
3.59
E
-
05
1.92
Transient receptor potential cation channel, subfamily V, member 1, transcript variant 3
NM_080706
TRPV1
4.14
E
-
05
2.25
Transient receptor potential cation channel, subfamily V, member 2
NM_016113
TRPV2
8.02
E
-
08
4.68
Transient receptor potential cation channel, subfamily V, member 3
NM_145068
TRPV3
4.64
E
-
01
1.35
Transient receptor potential cation channel, subfamily V, member 3
NM_145068
TRPV3
1.35
E
-
01
−2.39
Transient receptor potential cation channel, subfamily V, member 4, transcript variant 2
NM_147204
TRPV4
4.33
E
-
01
1.39
Transient receptor potential cation channel, subfamily V, member 5,  (cDNA clone MGC: 34269 IMAGE: 5186668)
BC034740
TRPV5
1.00
E
-
01
1.38
Transient receptor potential cation channel, subfamily V, member 5
NM_019841
TRPV5
3.14
E
-
01
−1.40
Transient receptor potential cation channel, subfamily V, member 6
NM_018646
TRPV6
1.57
E
-
01
−1.38
(p)
Voltage-gated sodium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Sodium channel, voltage-gated, type I, alpha subunit, transcript variant 2
NM_006920
SCN1A
1.98
E
-
01
1.54
Sodium channel, voltage-gated, type I, beta, transcript variant b
NM_199037
SCN1B
9.95
E
-
01
−1.00
Sodium channel, voltage-gated, type II, alpha subunit, transcript variant 1
NM_021007
SCN2A
4.16
E
-
01
1.62
5.00
Sodium channel, voltage-gated, type II, beta
NM_004588
SCN2B
3.61
E
-
01
−1.58
Sodium channel, voltage-gated, type II, beta
NM_004588
SCN2B
8.16
E
-
04
−2.41
Sodium channel, voltage-gated, type III, alpha subunit, transcript variant 1
NM_006922
SCN3A
2.87
E
-
01
−2.00
2.85
Sodium channel, voltage-gated, type III, alpha subunit, transcript variant 1
NM_006922
SCN3A
1.89
E
-
01
1.49
Sodium channel, voltage-gated, type III, beta, transcript variant 1
NM_018400
SCN3B
8.74
E
-
01
−1.06
4.70
Sodium channel, voltage-gated, type III, beta, transcript variant 1
NM_018400
SCN3B
1.57
E
-
01
−1.46
Sodium channel, voltage-gated, type III, beta, transcript variant 1
NM_018400
SCN3B
1.56
E
-
01
1.96
Sodium channel, voltage-gated, type IV, alpha subunit
NM_000334
SCN4A
1.62
E
-
08
9.91
Sodium channel, voltage-gated, type IV, beta, transcript variant 1
NM_174934
SCN4B
3.25
E
-
04
−3.66
Sodium channel, voltage-gated, type V, alpha subunit, transcript variant 1
NM_198056
SCN5A
2.43
E
-
08
14.10
Sodium channel, voltage-gated, type V, alpha subunit, transcript variant 2
NM_000335
SCN5A
4.93
E
-
02
1.95
Sodium channel, voltage-gated, type VII, alpha
NM_002976
SCN7A
4.49
E
-
03
1.63
Sodium channel, voltage-gated, type VII, alpha
NM_002976
SCN7A
2.07
E
-
01
1.72
Sodium channel, voltage gated, type VIII, alpha subunit, transcript variant 1
NM_014191
SCN8A
1.89
E
-
09
15.61
Sodium channel, voltage gated, type VIII, alpha subunit, transcript variant 1
NM_014191
SCN8A
4.06
E
-
07
11.23
Sodium channel, voltage-gated, type IX, alpha subunit
NM_002977
SCN9A
4.08
E
-
08
11.51
Sodium channel, voltage-gated, type IX, alpha subunit
NM_002977
SCN9A
1.62
E
-
01
1.66
Sodium channel, voltage-gated, type IX, alpha subunit
NM_002977
SCN9A
3.38
E
-
03
2.57
Sodium channel, voltage-gated, type X, alpha subunit
NM_006514
SCN10A
4.06
E
-
01
1.35
Sodium channel, voltage-gated, type XI, alpha subunit
NM_014139
SCN11A
3.02
E
-
01
1.57
Sodium channel, voltage-gated, type XI, alpha subunit [Source: HGNC Symbol; Acc: 10583]
ENST00000444237
SCN11A
8.83
E
-
03
1.94
(q)
Nonvoltage-gated sodium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Sodium channel, nonvoltage-gated 1 alpha, transcript variant 1
NM_001038
SCNN1A
1.33
E
-
09
51.49
−21.13
−10.71
Sodium channel, nonvoltage-gated 1, beta
NM_000336
SCNN1B
2.11
E
-
01
1.64
Sodium channel, nonvoltage-gated 1, beta
NM_000336
SCNN1B
5.52
E
-
01
1.09
Sodium channel, nonvoltage-gated 1, delta, transcript variant 1
NM_001130413
SCNN1D
8.43
E
-
02
1.49
Sodium channel, nonvoltage-gated 1, gamma
NM_001039
SCNN1G
2.33
E
-
01
1.59
Gamma subunit of epithelial amiloride-sensitive sodium channel
X87160
SCNN1G
3.99
E
-
01
1.27
(r)
Two-pore channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Two-pore segment channel 1, transcript variant 1
NM_001143819
TPCN1
6.20
E
-
04
−1.76
Two-pore segment channel 1, transcript variant 2
NM_017901
TPCN1
1.71
E
-
03
−2.10
Two-pore segment channel 1, transcript variant 2
NM_017901
TPCN1
3.55
E
-
04
−2.44
Two-pore segment channel 1, transcript variant 1
NM_001143819
TPCN1
8.06
E
-
03
−1.83
Two-pore segment channel 2
NM_139075
TPCN2
5.06
E
-
01
−1.15
(s)
Zinc-activated ligand-gated ion channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Zinc-activated ligand-gated ion channel
NM_180990
ZACN
9.24
E
-
02
1.45


### 3.2. Voltage-Gated Calcium Channels

Voltage-gated calcium channels are crucially involved in the Ca2+-influx thereby playing an important role in calcium signaling of virtually all cells. High-voltage-gated calcium channels include the neural N-type channel, the poorly defined brain-specific R-type channel, the closely related P/Q-type channel, and the dihydropyridine-sensitive L-type channels responsible for excitation-contraction coupling of skeletal, smooth, and cardiac muscles as well as for hormone secretion in endocrine cells (reviewed in [24]). While mainly permeable for calcium ions they also show a low permeability for sodium ions. Upon depolarization of the cell they mediate a calcium influx into the cell. The channels consist of the main alpha subunit as well as regulatory beta, alpha 2/delta, and gamma subunits. The α1 subunit forms the ion conducting pore while the associated subunits have several functions including modulation of gating [25].CACNA1A mutations are for example involved in ataxia [26]. We have analyzed their expression with 42 probes. During reprogramming 14 (33%) of them are significantly upregulated while only 1 (2%) is significantly downregulated. From iPSCs to neurons, as expected, neuronal alpha-subunits CACNA1D, CACNA1Eareupregulated together with several neuronal channel subunits (α2δ, β, and γ). In cardiomyocytes, solely the alpha subunit of the cardiac CACNA1Cis upregulated. Of note, none of the differentiated progeny downregulated any voltage-gated calcium channels.


### 3.3. Sperm-Associated Cation Channels

Sperm-associated cation channels or CatSper channels are calcium ion channels. They are flagellar proteins involved in sperm motility and therefore affect fertility [27]. During reprogramming to iPSCs, from seven used probes just one showed a significant downregulation and none had a significant upregulation. We observed nothing noteworthy in the differentiated progeny.


### 3.4. Nicotinic Acetylcholine Receptors

Nicotinic acetylcholine receptors play a role in interneuronal synapses and neuromuscular junctions. They are composed of five subunits as homomeric or heteromeric receptors. They are located at the postsynaptic site and upon binding of acetylcholine they allow the transmission of cations, especially sodium and potassium ions, in some versions also calcium ions. This leads to a depolarization of the membrane and triggers further signaling pathways [28]. Several acetylcholine receptors and subunits are thought to play roles in a variety of pathomechanisms, for example, psychiatric disorders, cardiovascular diseases, or cancer [29–31]. From 21 probes, 5 (24%) showed a significant upregulation while 3 (14%) showed a significant downregulation from keratinocytes to iPSCs. In neurons, solely the neuronal nicotinic acetylcholine receptor CHRNA6 alpha subunit was upregulated, none in cardiomyocytes.


### 3.5. Cyclic Nucleotide-Gated Channels

Cyclic nucleotide-gated channels form tetrameric channels which—upon binding of cGMP—allow a flow of cations. For that, these channels track the intracellular concentration of cNMPs to produce a voltage response [32]. Their major role is the depolarization of rod photoreceptors, but they are also found in other tissues like olfactory sensory neurons [33], testis, kidney, or heart [34] and play a role in cellular development such as neuronal growth cone guidance [35]. Defects in these genes are reported to cause retinitis pigmentosa [36]. From 7 used probes one showed a significant upregulation and one showed a significant downregulation (both 14%) during reprogramming, while none was differentially regulated in differentiated neurons or cardiomyocytes.


### 3.6. GABA Receptors

GABA (gamma-aminobutyric acid) receptors are ligand-gated chloride channels. Since GABA is the main inhibitory neurotransmitter in the central nervous system GABA receptors play an important role for the brain function. The receptors are composed of five subunits which form heteromers. The GABA receptors are a drug target for anesthetics and other psychoactive drugs. We have analyzed 29 probes within GABA receptor subunits. From keratinocytes to iPSCs, 6 (21%) of them are significantly upregulated while just one (3%) is significantly downregulated. Interestingly, none was up- or downregulated in differentiated neurons, whileGABRB3 was downregulated  and GABRP was upregulated in cardiomyocytes. Up to now, more or less nothing is known about GABA receptors or their subunits in cardiac cells.


### 3.7. Glycine Receptors

Glycine receptors are inhibitory receptors of the postsynaptic site. They are activated by glycine and mediate an influx of chloride ions. Accordingly, GlyRs regulate not only the excitability of motor and sensory neurons but are also essential for the processing of photoreceptor signals, neuronal development, and inflammatory pain sensitization [37]. The heteromeric pore is formed by five subunits. Concerning their role in pathomechanisms, it was reported that mutations are causing hyperekplexia (also known as startle disease) [38]. We have analyzed 7 probes and none of them was significantly altered in hiPSCs. Transcript levels for the alpha2 subunit and the beta subunit were highly upregulated in differentiated neurons, pointing to their functional role in the nervous system.


### 3.8. Ionotropic Glutamate Receptors

Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Therefore, ionotropic glutamate receptors play a key role for learning and memory processes. They are located in the postsynaptic membrane and are composed of several heteromeric subunits. Ionotropic glutamate receptors are further divided into AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate), NMDA (N-Methyl-D-aspartate) or kainate receptors depending on their sensitivity for the agonists. From 36 probes, 5 (14%) showed a significantly increased expression and 2 (6%) showed a decreased expression in iPSCs compared to keratinocytes. As expected, several subunits were upregulated in neurons (none downregulated). None was upregulated in cardiomyocytes, while the kainate subtypeGRIK5 was downregulated.


### 3.9. Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels

Hyperpolarization-activated cyclic nucleotide-gated channels are homodimers or heterodimers and form a hyperpolarization-activated potassium channel. CNG channels display a very complex heteromeric structure with various subunits and domains that play a critical role in their function [39]. They contribute to pacemaker currents in the heart [40] but are also found in neurons [41]. We have analyzed 5 probes and 3 (60%) of them showed a significant upregulation while none was downregulated after reprogramming. In neurons the HCN3 channel transcript was upregulated, which plays a role in several neuronal functions including excitability of basal ganglia output neurons [42]. Although HCN4 for example plays a critical role in the conduction system of the heart, we did not observe a specific regulation in cardiomyocytes.


### 3.10. Serotonin Receptors

Serotonin (or 5-hydroxytryptamine) receptors are ligand-gated receptors mainly found presynaptically in neurons. The type 3 receptor is the only ion channel while the other serotonin receptors are G-protein-coupled receptors. It forms a heteropentameric pore which upon activation by serotonin allows the flow of sodium and potassium, leading to a depolarization. Serotonin receptors modulate neuronal function and are therefore involved in various brain functions. The analysis of 6 probes for type 3 serotonin receptors showed a significant upregulation of 2 (33%, both forHTR3A) probes while none was downregulated in hiPSCs. Although we expected serotonin receptors to be upregulated during neuronal differentiation, no subunit was upregulated in neurons or cardiomyocytes, while only the receptor transcript for HTR3Awas downregulated in neurons.


### 3.11. Voltage-Gated Potassium Channels

Voltage-gated potassium channels are composed of a large group of subunits with different characteristics concerning for example their inactivation speed. Functional channels are formed by heterotetramers. The channels are highly specific for potassium with a low affinity for sodium or other cations. Voltage-gated potassium channels are responsible for the repolarization of excitable cells following the sodium-mediated excitation of an action potential and are therefore found in neurons and other cells displaying action potentials. We have analyzed 81 probes. From keratinocytes to hiPSCs, 25 (31%) were significantly upregulated while only 3 (4%) were significantly downregulated. In neurons, several subunits were upregulated includingKCNB1, coding for Kv2.1 and KCND2, both are better known for their role in cardiac cell excitability as well as KCNF1, KCNH8, and KCNIP1, all known for their contribution in neuronal excitability [43]. It should be noted that KCNT1 is actually sodium activated but is included in the alphabetical list for a better overview. Further, several “S” subunits were upregulated (KCNS2 in neurons) or downregulated (KCNS3 in neurons; KCNS1 and 3 in cardiomyocytes). These subunits are unable to form functional channels as homotetramers but instead heterotetramerize with other alpha-subunits to form conductive channels. These subunits are involved in modifying the channels response and conductivity [44]. Few is known about distinct roles in other tissues, but they were associated with for example, pain modulation [45] or airway responsiveness [46].


### 3.12. Inwardly Rectifying Potassium Channels

Inwardly rectifying potassium channels have a higher tendency to allow the flow of potassium ions into the cell rather than to the outside of the cell. Therefore, they play an important role in the maintenance of the resting membrane potential. Their activation is constitutive or controlled by ATP binding and G-proteins [47]. Functional channels are formed as homo- or heterotetramers. These channels can be found predominantly in neurons, cardiac myocytes, the pancreas, or the kidneys. From 20 analyzed probes in hiPSCs compared to keratinocytes, 8 (40%) showed a significant upregulation and 3 (15%) were significantly downregulated. The GIRK2 channel encoded by KCNJ6 is upregulated in neurons playing multiple roles in various tissues including the  pancreas and brain [48, 49] and is associated with epileptic seizures in mice lacking the gene [50]. On the other hand, Kir6.1, encoded by KCNJ8, is upregulated in cardiomyocytes and has been reported to be involved in the pathogenesis of cardiac arrest in the early repolarization syndrome [51].


### 3.13. Two-P Potassium Channels

Two-P potassium channels contain two pore-forming P domains. After dimerization they form an outward rectifying potassium channel. They can be found in several tissues and are activated by various chemical or physical means (TRAAK channels). We have analyzed 23 probes. 4 (17%) of them were significantly upregulated while 4 (17%) were significantly downregulated. In neuronsKCNK3, vital for setting the resting membrane potential and primary target for volatile anesthetics [52] as well as KCNK4,which is mechanically gated and contributes to axonal pathfinding, growth cone motility, and neurite elongation, as well as possibly having a role in touch or pain detection [53, 54], were upregulated. KCNK5 and 6 were downregulated. In cardiomyocytes, downregulation of KCNK5 and 12 was observed.


### 3.14. Calcium-Activated Potassium Channels

Calcium-activated potassium channels are mostly activated by intracellular calcium; some family members are also voltage gated. The family consists of large, intermediate, and small conductance family members. Channels are formed by two units (KCNM family) or most commonly four units (KCNN family). They are involved in, for example, afterhyperpolarization following the action potential and are predominantly found in neurons. Additionally, they are known to play different roles in cellular mechanisms, including stem cell biology [4–6, 55]. We have analyzed 18 probes of which 9 (50%) were significantly upregulated and none was significantly downregulated after reprogramming. In neurons, solely KCNN2 was downregulated, while in cardiomyocytes KCNMA1, encoding the large conductance BK-channel, involved in heart rate regulation [56], was upregulated.


### 3.15. P2X Receptors

P2X receptors are receptors for extracellular ATP and upon activation open a channel for ions, predominantly calcium. The channel is formed by homo- or heterotrimers. They are found in several tissues, mainly in the nervous system and muscle tissue. They are involved in a range of physiological processes such as modulation of synaptic transmission, vascular tone, cardiac rhythm, and contractility and immune response [57–61]. In stem cells an influence of P2X receptors on embryonic stem cell proliferation was reported [62]. From the 9 analyzed probes 1 (11%) was significantly upregulated and none downregulated. None of these receptors/channels was regulated in differentiated progeny.


### 3.16. Transient Receptor Potential Channels

Transient receptor potential channels (TRP channels) are nonselective cation channels. They show different preferences for cations, as well as different activation mechanisms and functions. TRP channels are broadly expressed throughout the organism and mediate multiple functions. These include amongst others sensor activity for a wide range of hypertrophic stimuli and mutations inTRPM4 are now recognized as causes of human cardiac conduction disorders (reviewed in [63]). Furthermore, TRP channels are related to the onset or progression of several diseases, and defects in the genes encoding TRP channels (so-called “TRP channelopathies”) underlie certain neurodegenerative disorders due to their abnormal Ca2+ signaling properties (reviewed in [64]). Additionally, TRP channels influence stem cell differentiation and survival [65, 66] and are involved in neuronal-stem-cell-derived development [67]. We have analyzed 40 probes. After reprogramming, 11 (28%) of them were significantly upregulated and none was significantly downregulated. In neurons, none of these channels was noteworthily regulated while solely TRPC3 was upregulated in cardiomyocytes, reported to be involved in conduction disturbances induced by adenosine receptor A1AR by enhanced  Ca2+ entry through the TRPC3 channel [68].


### 3.17. Voltage-Gated Sodium Channels

Voltage-gated sodium channels consist of a main alpha unit and some optional modulating or regulatory subunits. They are highly selective for sodium and are involved in a variety of cellular functions including action potential formation [69]. From 24 probes we have analyzed, 6 (25%) were significantly upregulated and two (8%) were significantly downregulated from keratinocytes to iPS cells. These channels seem to be expressed in different kinds of stem cells and during development [70–72]. It was further reported that, for example, SCN5A, highly upregulated in iPS cells, is involved in cancer stem cell invasion [73]. SCN2A, SCN3A, and SCN3Bwere upregulated in neurons, described to be involved in neuronal excitation and epilepsy pathogenesis [74]. Although voltage-gated sodium channels play multiple roles also in the cardiac system [70, 75, 76], we observed no changes of this channel family in cardiomyocytes.


### 3.18. Nonvoltage-Gated Sodium Channels

Epithelial nonvoltage-gated sodium channels are amiloride sensitive. They form heterotrimers and are involved in ion and fluid transport across epithelia in several organs. We have analyzed 6 probes and one (17%) of them was significantly upregulated while none was significantly downregulated. Interestingly, the upregulatedSCNN1A in iPS cells was subsequently downregulated both in neurons and cardiomyocytes, pointing to a possible function in stem cells. Of note, it was shown already that repression of pluripotency by retinoic acid represses the SCNN1A gene together with several other pluripotency factors [77].


### 3.19. Two-Pore Channels

Two-pore channels are cation-selective ion channels activated by the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). Upon activation calcium is released from intracellular stores [78]. We have analyzed 5 probes and while none of them was significantly upregulated two (40%) were significantly downregulated from keratinocytes to iPS cells. None of these channels was regulated in neurons or cardiomyocytes.


### 3.20. Zinc-Activated Ligand-Gated Ion Channels

The zinc-activated ligand-gated ion channel is activated upon binding of zinc. Until now just one family member is known that is expressed in several tissues [79]. Its exact function is not known. The expression was not significantly altered as shown by one probe in all cells.


## 3.1. Differential Expression of Ion Channels in hiPSCs Compared to Keratinocytes

We first compared the expression of various ion channel families from keratinocytes to hiPSCs and from hiPSCs to cardiomyocytes and neurons, respectively. From the 387 probes (Table1) binding in ion channel genes from parental keratinocytes to hiPSCs, 101 (26%) showed a significant increase in expression (fold change > 2, P<0.05; labeled in bold) while 23 (6%) showed a significant decrease (fold change > −2, P<0.05; labeled in italic). In a second step differentially regulated ion channels from hiPSCs to hiPSC-derived neurons were investigated and we found 29 ion channel transcripts to be upregulated (fold change > 2; labeled in bold) while 6 showed a significant decrease (fold change > −2; labeled in italic). For cardiomyocytes, mRNA levels of only 7 ion channel members were upregulated (fold change > 2; labeled in bold) and 10 mRNA levels showed a significant decrease (fold change > −2; labeled in italic).Table 1
The expression levels for ion channel genes were compared in hiPSCs (9 samples) and keratinocytes (6 samples) via microarray. Gene names, accession numbers, and gene symbols are shown together with the corresponding fold change andP values. Significant changes (defined as fold change > 2, P<0.05) are labeled in bold for upregulation or italic for downregulation. Accession numbers refer to the NCBI or Ensembl (numbers starting with ENST) databases. Analyses of hiPSC-derived neurons or hiPSC-derived cardiomyocytes were performed using published data sets from GSE34879 (neurons) and GSE17579 (cardiomyocytes). These data sets already contain both iPSCs and differentiated progeny. Fold changes > 2 (marked bold) and <−2 (marked italic) are shown in the respective columns.
(a)
Voltage-gated calcium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Calcium channel, voltage-dependent, P/Q type, alpha 1A subunit, transcript variant 1
NM_000068
CACNA1A
2.26
E
-
01
−1.32
Calcium channel, voltage-dependent, N type, alpha 1B subunit
NM_000718
CACNA1B
7.27
E
-
01
−1.10
Calcium channel, voltage-dependent, N type, alpha 1B subunit [Source: HGNC Symbol; Acc: 1389]
ENST00000277550
CACNA1B
7.15
E
-
01
−1.14
Calcium channel, voltage-dependent, N type, alpha 1B subunit
NM_000718
CACNA1B
6.32
E
-
09
6.82
Calcium channel, voltage-dependent, N type, alpha 1B subunit [Source: HGNC Symbol; Acc: 1389]
ENST00000277551
CACNA1B
3.32
E
-
02
−1.57
Calcium channel, voltage-dependent, L type, alpha 1C subunit, transcript variant 18
NM_000719
CACNA1C
6.77
E
-
02
−1.37
Calcium channel, voltage-dependent, L type, alpha 1C subunit, transcript variant 18
NM_000719
CACNA1C
5.72
E
-
03
2.37
2.94
Calcium channel, voltage-dependent, L type, alpha 1D subunit, transcript variant 1
NM_000720
CACNA1D
3.83
E
-
01
1.58
Calcium channel, voltage-dependent, R type, alpha 1E subunit, transcript variant 3
NM_000721
CACNA1E
3.10
E
-
02
−4.48
2.08
Calcium channel, voltage-dependent, R type, alpha 1E subunit [Source: HGNC Symbol; Acc: 1392]
ENST00000524607
CACNA1E
8.83
E
-
01
1.05
Calcium channel, voltage-dependent, L type, alpha 1F subunit
NM_005183
CACNA1F
8.92
E
-
01
1.02
Calcium channel, voltage-dependent, T type, alpha 1G subunit, transcript variant 15
NM_198397
CACNA1G
6.42
E
-
01
−1.12
4.60
Calcium channel, voltage-dependent, T type, alpha 1G subunit, transcript variant 1
NM_018896
CACNA1G
5.37
E
-
07
6.96
Calcium channel, voltage-dependent, T type, alpha 1H subunit, transcript variant 1
NM_021098
CACNA1H
7.38
E
-
10
6.78
Calcium channel, voltage-dependent, T type, alpha 1I subunit, transcript variant 1
NM_021096
CACNA1I
2.22
E
-
11
37.25
Calcium channel, voltage-dependent, T type, alpha 1I subunit, transcript variant 1
NM_021096
CACNA1I
7.56
E
-
02
−1.56
Calcium channel, voltage-dependent, L type, alpha 1S subunit
NM_000069
CACNA1S
5.22
E
-
02
−1.97
Calcium channel, voltage-dependent, alpha 2/delta subunit 1
NM_000722
CACNA2D1
1.38
E
-
09
9.65
Calcium channel, voltage-dependent, alpha 2/delta subunit 2, transcript variant 1
NM_001005505
CACNA2D2
3.30
E
-
10
62.50
2.02
Calcium channel, voltage-dependent, alpha 2/delta subunit 3
NM_018398
CACNA2D3
5.14
E
-
05
5.42
2.55
Calcium channel, voltage-dependent, alpha 2/delta subunit 3
AF516696
CACNA2D3
4.68
E
-
11
33.67
Calcium channel, voltage-dependent, alpha 2/delta subunit 4
NM_172364
CACNA2D4
2.95
E
-
01
−1.41
Calcium channel, voltage-dependent, beta 1 subunit, transcript variant 3
NM_199248
CACNB1
4.31
E
-
01
−1.14
Calcium channel, voltage-dependent, beta 1 subunit, transcript variant 1
NM_000723
CACNB1
8.02
E
-
01
−1.02
Calcium channel, voltage-dependent, beta 1 subunit, transcript variant 1
NM_000723
CACNB1
6.22
E
-
01
1.04
cDNA FLJ45229 fis, clone BRCAN2020972,
AK128769
CACNB2
9.78
E
-
01
1.02
Calcium channel, voltage-dependent, beta 2 subunit, transcript variant 1
NM_000724
CACNB2
4.71
E
-
02
3.45
Calcium channel, voltage-dependent, beta 3 subunit, transcript variant 1
NM_000725
CACNB3
3.55
E
-
02
−1.93
9.56
Calcium channel, voltage-dependent, beta 3 subunit, transcript variant 1
NM_000725
CACNB3
6.61
E
-
01
1.09
Calcium channel, voltage-dependent, beta 4 subunit, transcript variant 1
NM_001005747
CACNB4
1.33
E
-
03
4.43
Calcium channel, voltage-dependent, gamma subunit 1
NM_000727
CACNG1
9.46
E
-
01
1.02
Calcium channel, voltage-dependent, gamma subunit 2
NM_006078
CACNG2
4.19
E
-
01
−1.29
Calcium channel, voltage-dependent, gamma subunit 2
NM_006078
CACNG2
7.91
E
-
01
1.09
Calcium channel, voltage-dependent, gamma subunit 3
NM_006539
CACNG3
2.21
E
-
01
−1.95
Calcium channel, voltage-dependent, gamma subunit 4
NM_014405
CACNG4
4.93
E
-
01
1.14
Calcium channel, voltage-dependent, gamma subunit 5
NM_145811
CACNG5
7.49
E
-
01
−1.13
Calcium channel, voltage-dependent, gamma subunit 5 [Source: HGNC Symbol; Acc: 1409]
ENST00000169565
CACNG5
2.19
E
-
01
−1.56
Calcium channel, voltage-dependent, gamma subunit 6, transcript variant 1
NM_145814
CACNG6
5.56
E
-
11
46.40
Calcium channel, voltage-dependent, gamma subunit 7
NM_031896
CACNG7
3.54
E
-
13
1439.36
3.37
Calcium channel, voltage-dependent, gamma subunit 7
NM_031896
CACNG7
1.82
E
-
01
1.26
Calcium channel, voltage-dependent, gamma subunit 8
NM_031895
CACNG8
2.01
E
-
01
1.43
Calcium channel, voltage-dependent, gamma subunit 8
NM_031895
CACNG8
1.18
E
-
09
9.70
(b)
Sperm-associated cation channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Cation channel, sperm associated 1
NM_053054
CATSPER1
3.26
E
-
01
1.51
Cation channel, sperm associated 2, transcript variant 2
NM_172095
CATSPER2
1.32
E
-
04
−2.78
Cation channel, sperm associated 2, transcript variant 4
NM_172097
CATSPER2
3.12
E
-
02
−1.78
Cation channel, sperm associated 3
NM_178019
CATSPER3
1.50
E
-
03
1.93
Cation channel, sperm associated 4
NM_198137
CATSPER4
2.51
E
-
01
1.48
Cation channel, sperm-associated, beta
NM_024764
CATSPERB
4.38
E
-
01
−1.25
Cation channel, sperm-associated, gamma
NM_021185
CATSPERG
3.56
E
-
01
1.34
(c)
Nicotinic acetylcholine receptors
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Cholinergic receptor, nicotinic, alpha 1 (muscle), transcript variant 1
NM_001039523
CHRNA1
8.06
E
-
01
−1.10
Cholinergic receptor, nicotinic, alpha 1 (muscle),  (cDNA clone IMAGE: 4124038), with apparent retained intron
BC006314
CHRNA1
4.64
E
-
01
1.47
Cholinergic receptor, nicotinic, alpha 2 (neuronal)
NM_000742
CHRNA2
6.05
E
-
01
−1.30
Cholinergic receptor, nicotinic, alpha 3, transcript variant 1
NM_000743
CHRNA3
1.84
E
-
10
34.22
Cholinergic receptor, nicotinic, alpha 4
NM_000744
CHRNA4
6.79
E
-
01
1.15
Cholinergic receptor, nicotinic, alpha 4 (neuronal), exon 1
X89741
CHRNA4
2.79
E
-
02
−2.53
Cholinergic receptor, nicotinic, alpha 5
NM_000745
CHRNA5
4.03
E
-
05
3.41
Cholinergic receptor, nicotinic, alpha 6, transcript variant 1
NM_004198
CHRNA6
2.23
E
-
01
−1.27
2.21
Cholinergic receptor, nicotinic, alpha 7, transcript variant 1
NM_000746
CHRNA7
4.61
E
-
04
1.86
Cholinergic receptor, nicotinic, alpha 7, transcript variant 2
NM_001190455
CHRNA7
1.56
E
-
11
13.24
Cholinergic receptor, nicotinic, alpha 9
NM_017581
CHRNA9
6.30
E
-
06
6.15
Cholinergic receptor, nicotinic, alpha 10
NM_020402
CHRNA10
1.57
E
-
02
1.57
Cholinergic receptor, nicotinic, beta 1 (muscle)
NM_000747
CHRNB1
8.07
E
-
04
−2.47
Cholinergic receptor, nicotinic, beta 1 (muscle)
NM_000747
CHRNB1
8.87
E
-
03
−1.92
Cholinergic receptor, nicotinic, beta 2 (neuronal)
NM_000748
CHRNB2
6.03
E
-
04
−3.01
Cholinergic receptor, nicotinic, beta 2 (neuronal) [Source: HGNC Symbol; Acc: 1962]
ENST00000368476
CHRNB2
2.98
E
-
09
32.05
Cholinergic receptor, nicotinic, beta 3
NM_000749
CHRNB3
5.91
E
-
01
1.12
Cholinergic receptor, nicotinic, beta 4
NM_000750
CHRNB4
1.76
E
-
02
4.20
Cholinergic receptor, nicotinic, delta
NM_000751
CHRND
9.84
E
-
01
1.01
Cholinergic receptor, nicotinic, epsilon
NM_000080
CHRNE
3.66
E
-
01
−1.20
Cholinergic receptor, nicotinic, gamma
NM_005199
CHRNG
6.70
E
-
01
1.14
(d)
Cyclic nucleotide-gated channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Cyclic nucleotide-gated channel alpha 1, transcript variant 2
NM_000087
CNGA1
7.14
E
-
01
1.15
Cyclic nucleotide-gated channel alpha 1, transcript variant 2
NM_000087
CNGA1
1.18
E
-
02
2.00
Cyclic nucleotide-gated channel alpha 3, transcript variant 1
NM_001298
CNGA3
2.00
E
-
01
1.21
Cyclic nucleotide-gated channel alpha 4
NM_001037329
CNGA4
2.78
E
-
01
1.82
Cyclic nucleotide-gated channel beta 1, transcript variant 1
NM_001297
CNGB1
9.22
E
-
03
−2.05
Cyclic nucleotide-gated channel beta 1, transcript variant 1
NM_001297
CNGB1
6.36
E
-
01
-
1.13
Cyclic nucleotide-gated channel beta 3
NM_019098
CNGB3
2.93
E
-
01
1.78
(e)
GABA receptors
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Gamma-aminobutyric acid (GABA) A receptor, alpha 1, transcript variant 1
NM_000806
GABRA1
1.26
E
-
01
1.41
Gamma-aminobutyric acid (GABA) A receptor, alpha 1, transcript variant 1
NM_000806
GABRA1
8.87
E
-
01
1.05
Gamma-aminobutyric acid (GABA) A receptor, alpha 2, transcript variant 1
NM_000807
GABRA2
9.70
E
-
02
1.70
Gamma-aminobutyric acid (GABA) A receptor, alpha 2, transcript variant 1
NM_000807
GABRA2
4.49
E
-
01
1.48
Gamma-aminobutyric acid (GABA) A receptor, alpha 3
NM_000808
GABRA3
2.10
E
-
01
1.43
Gamma-aminobutyric acid (GABA) A receptor, alpha 4, transcript variant 1
NM_000809
GABRA4
3.76
E
-
01
1.43
Gamma-aminobutyric acid (GABA) A receptor, alpha 4, transcript variant 1
NM_000809
GABRA4
8.30
E
-
01
1.05
Gamma-aminobutyric acid (GABA) A receptor, alpha 5, transcript variant 1
NM_000810
GABRA5
1.09
E
-
08
14.41
Gamma-aminobutyric acid (GABA) A receptor, alpha 6
NM_000811
GABRA6
1.69
E
-
01
1.23
Gamma-aminobutyric acid (GABA) A receptor, beta 1
NM_000812
GABRB1
1.14
E
-
01
1.43
Gamma-aminobutyric acid (GABA) A receptor, beta 2, transcript variant 2
NM_000813
GABRB2
1.27
E
-
02
1.94
Gamma-aminobutyric acid (GABA) A receptor, beta 3, transcript variant 1
NM_000814
GABRB3
6.70
E
-
10
85.93
−4.49
Gamma-aminobutyric acid (GABA) A receptor, beta 3, transcript variant 1
NM_000814
GABRB3
1.15
E
-
09
115.69
Gamma-aminobutyric acid (GABA) A receptor, delta
NM_000815
GABRD
6.26
E
-
02
3.02
Gamma-aminobutyric acid (GABA) A receptor, epsilon
NM_004961
GABRE
5.83
E
-
05
−5.47
Gamma-aminobutyric acid (GABA) A receptor, Gamma 1
NM_173536
GABRG1
1.78
E
-
01
1.24
Gamma-aminobutyric acid (GABA) A receptor, Gamma 1
NM_173536
GABRG1
1.70
E
-
02
2.19
Gamma-aminobutyric acid (GABA) A receptor, Gamma 2, transcript variant 1
NM_198904
GABRG2
6.02
E
-
01
1.14
Gamma-aminobutyric acid (GABA) A receptor, Gamma 2, transcript variant 2
NM_000816
GABRG2
5.28
E
-
02
1.72
Gamma-aminobutyric acid (GABA) A receptor, Gamma 2, transcript variant 2
NM_000816
GABRG2
9.47
E
-
09
8.41
Gamma-aminobutyric acid (GABA) A receptor, Gamma 3
NM_033223
GABRG3
1.99
E
-
01
2.00
Gamma-aminobutyric acid (GABA) A receptor, Gamma 3
NM_033223
GABRG3
1.04
E
-
01
1.61
Gamma-aminobutyric acid (GABA) A receptor, pi
NM_014211
GABRP
6.62
E
-
01
−1.12
17.25
Gamma-aminobutyric acid (GABA) receptor, theta
NM_018558
GABRQ
1.60
E
-
01
1.56
Gamma-aminobutyric acid (GABA) receptor, theta
NM_018558
GABRQ
4.76
E
-
01
−1.27
Gamma-aminobutyric acid (GABA) receptor, theta [Source: HGNC Symbol; Acc: 14454]
ENST00000370306
GABRQ
8.22
E
-
09
52.17
Gamma-aminobutyric acid (GABA) receptor, rho 1
NM_002042
GABRR1
8.94
E
-
01
−1.04
Gamma-aminobutyric acid (GABA) receptor, rho 2
NM_002043
GABRR2
2.83
E
-
01
1.54
Gamma-aminobutyric acid (GABA) receptor, rho 3
NM_001105580
GABRR3
3.05
E
-
01
−1.34
(f)
Glycine receptors
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Glycine receptor, alpha 1, transcript variant 2
NM_000171
GLRA1
5.47
E
-
01
−1.29
Glycine receptor, alpha 2, transcript variant 1
NM_002063
GLRA2
1.17
E
-
01
1.42
11.41
Glycine receptor, alpha 3, transcript variant 1
NM_006529
GLRA3
5.16
E
-
01
−1.26
Glycine receptor, alpha 3 [Source: HGNC Symbol; Acc: 4328]
ENST00000274093
GLRA3
8.33
E
-
02
1.64
Glycine receptor, alpha 3, transcript variant 1
NM_006529
GLRA3
1.46
E
-
01
1.41
Glycine receptor, alpha 4, transcript variant 1
NM_001024452
GLRA4
7.75
E
-
01
1.17
Glycine receptor, beta, transcript variant 1
NM_000824
GLRB
6.38
E
-
02
−1.69
6.61
(g)
Ionotropic glutamate receptors
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Glutamate receptor, ionotropic, AMPA 1, transcript variant 1
NM_000827
GRIA1
7.65
E
-
01
−1.20
2.06
Glutamate receptor, ionotropic, AMPA 2, transcript variant 1
NM_000826
GRIA2
2.87
E
-
01
−1.87
21.26
Glutamate receptor, ionotropic, AMPA 2, transcript variant 1
NM_000826
GRIA2
2.72
E
-
01
1.33
Glutamate receptor, ionotropic, AMPA 2, transcript variant 1
NM_000826
GRIA2
6.54
E
-
01
1.22
Glutamate receptor, ionotropic, AMPA 3, transcript variant 2
NM_000828
GRIA3
5.05
E
-
01
1.26
Glutamate receptor, ionotropic, AMPA 3 [Source: HGNC Symbol; Acc: 4573]
ENST00000371264
GRIA3
1.14
E
-
01
1.50
Glutamate receptor, ionotropic, AMPA 3, transcript variant 2
NM_000828
GRIA3
9.05
E
-
01
−1.05
Glutamate receptor, ionotropic, AMPA 4, transcript variant 1
NM_000829
GRIA4
2.30
E
-
02
1.80
3.73
Glutamate receptor, ionotropic, delta 1
NM_017551
GRID1
1.82
E
-
01
1.50
Glutamate receptor, ionotropic, delta 1
NM_017551
GRID1
5.08
E
-
05
3.63
Glutamate receptor, ionotropic, delta 2
NM_001510
GRID2
7.64
E
-
01
−1.11
Glutamate receptor, ionotropic, delta 2
NM_001510
GRID2
5.55
E
-
09
55.66
Glutamate receptor, ionotropic, kainate 1, transcript variant 1
NM_000830
GRIK1
1.64
E
-
01
1.29
2.58
Glutamate receptor, ionotropic, kainate 2, transcript variant 3
NM_001166247
GRIK2
1.42
E
-
01
1.56
2.53
Glutamate receptor, ionotropic, kainate 2, transcript variant 1
NM_021956
GRIK2
1.14
E
-
01
−2.01
Glutamate receptor, ionotropic, kainate 2, transcript variant 2
NM_175768
GRIK2
7.80
E
-
01
1.08
Glutamate receptor, ionotropic, kainate 3
NM_000831
GRIK3
1.58
E
-
01
1.64
Glutamate receptor, ionotropic, kainate 3
NM_000831
GRIK3
6.15
E
-
10
22.64
Glutamate receptor, ionotropic, kainate 4 [Source: HGNC Symbol; Acc: 4582]
ENST00000527524
GRIK4
1.77
E
-
11
18.10
Glutamate receptor, ionotropic, kainate 4
NM_014619
GRIK4
5.73
E
-
02
2.54
Glutamate receptor, ionotropic, kainate 5
NM_002088
GRIK5
2.65
E
-
03
1.79
−2.41
Glutamate receptor, ionotropic, N-methyl D-aspartate 1, transcript variant NR1-3
NM_007327
GRIN1
1.93
E
-
02
−3.02
2.69
Glutamate receptor, ionotropic, N-methyl D-aspartate 1, transcript variant NR1-3
NM_007327
GRIN1
6.01
E
-
02
−2.45
Glutamate receptor, ionotropic, N-methyl D-aspartate 1, transcript variant NR1-3
NM_007327
GRIN1
3.86
E
-
01
−1.65
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A, transcript variant 2
NM_000833
GRIN2A
6.54
E
-
01
1.18
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A, transcript variant 2
NM_000833
GRIN2A
9.21
E
-
01
−1.02
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A, transcript variant 1
NM_001134407
GRIN2A
3.32
E
-
10
29.85
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A, transcript variant 2
NM_000833
GRIN2A
2.63
E
-
01
1.55
Glutamate receptor, ionotropic, N-methyl D-aspartate 2B
NM_000834
GRIN2B
6.64
E
-
01
−1.26
Glutamate receptor, ionotropic, N-methyl D-aspartate 2C
NM_000835
GRIN2C
8.01
E
-
01
−1.08
Glutamate receptor, ionotropic, N-methyl D-aspartate 2C
NM_000835
GRIN2C
5.01
E
-
01
1.13
Glutamate receptor, ionotropic, N-methyl D-aspartate 2D
NM_000836
GRIN2D
4.69
E
-
02
−1.82
Glutamate receptor, ionotropic, N-methyl-D-aspartate 3A
NM_133445
GRIN3A
3.28
E
-
01
−1.41
Glutamate receptor, ionotropic, N-methyl-D-aspartate 3B
NM_138690
GRIN3B
9.36
E
-
01
−1.02
Glutamate receptor, ionotropic, N-methyl D-aspartate-associated protein 1 (glutamate binding), transcript variant 1
NM_000837
GRINA
3.68
E
-
04
−2.05
2.05
NMDA receptor glutamate-binding chain (hnrgw), partial
U44954
GRINA
3.06
E
-
04
−1.81
(h)
Hyperpolarization-activated cyclic nucleotide-gated channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 1
NM_021072
HCN1
3.47
E
-
11
52.85
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 1
NM_021072
HCN1
1.01
E
-
08
9.91
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 2
NM_001194
HCN2
5.36
E
-
02
−1.63
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 3
NM_020897
HCN3
1.98
E
-
02
2.12
6.56
Hyperpolarization-activated cyclic nucleotide-gated potassium channel 4
NM_005477
HCN4
1.01
E
-
01
−1.66
(i)
Serotonin receptors
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
5-hydroxytryptamine (serotonin) receptor 3A, transcript variant 1
NM_213621
HTR3A
1.99
E
-
03
2.77
−2.20
5-hydroxytryptamine (serotonin) receptor 3A, transcript variant 1
NM_213621
HTR3A
2.63
E
-
11
11.11
5-hydroxytryptamine (serotonin) receptor 3B
NM_006028
HTR3B
1.99
E
-
01
−1.54
5-hydroxytryptamine (serotonin) receptor 3, family member C
NM_130770
HTR3C
4.81
E
-
01
1.34
5-hydroxytryptamine (serotonin) receptor 3 family member D, transcript variant 2
NM_182537
HTR3D
4.75
E
-
01
−1.37
5-hydroxytryptamine (serotonin) receptor 3, family member E
NM_182589
HTR3E
1.52
E
-
01
−1.44
(j)
Voltage-gated potassium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Potassium voltage-gated channel, shaker-related subfamily, member 1 (episodic ataxia with myokymia)
NM_000217
KCNA1
1.64
E
-
01
2.00
Potassium voltage-gated channel, shaker-related subfamily, member 1 (episodic ataxia with myokymia)
NM_000217
KCNA1
1.31
E
-
01
1.87
Potassium voltage-gated channel, shaker-related subfamily, member 2, transcript variant 2
NM_001204269
KCNA2
8.55
E
-
02
1.33
Potassium voltage-gated channel, shaker-related subfamily, member 2, transcript variant 1
NM_004974
KCNA2
8.33
E
-
01
1.06
Potassium voltage-gated channel, shaker-related subfamily, member 3
NM_002232
KCNA3
2.43
E
-
01
1.76
Potassium voltage-gated channel, shaker-related subfamily, member 4
NM_002233
KCNA4
5.75
E
-
01
1.11
Potassium voltage-gated channel, shaker-related subfamily, member 5
NM_002234
KCNA5
1.76
E
-
04
4.11
5.63
Potassium voltage-gated channel, shaker-related subfamily, member 6
NM_002235
KCNA6
7.20
E
-
02
2.28
Potassium voltage-gated channel, shaker-related subfamily, member 7
NM_031886
KCNA7
8.53
E
-
03
3.67
Potassium voltage-gated channel, shaker-related subfamily, member 7
NM_031886
KCNA7
1.04
E
-
01
2.39
Potassium voltage-gated channel, shaker-related subfamily, member 10
NM_005549
KCNA10
3.32
E
-
01
−1.62
Potassium voltage-gated channel, shaker-related subfamily, beta member 1, transcript variant 2
NM_003471
KCNAB1
2.70
E
-
01
1.46
Potassium voltage-gated channel, shaker-related subfamily, beta member 1, transcript variant 2
NM_003471
KCNAB1
3.60
E
-
02
2.42
Potassium voltage-gated channel, shaker-related subfamily, beta member 1, transcript variant 2
NM_003471
KCNAB1
7.87
E
-
02
3.06
Potassium voltage-gated channel, shaker-related subfamily, beta member 2, transcript variant 1
NM_003636
KCNAB2
5.35
E
-
01
−1.35
Potassium voltage-gated channel, shaker-related subfamily, beta member 2, transcript variant 1
NM_003636
KCNAB2
2.20
E
-
01
1.26
Potassium voltage-gated channel, shaker-related subfamily, beta member 3 [Source: HGNC Symbol; Acc: 6230]
ENST00000303790
KCNAB3
8.14
E
-
02
1.62
Potassium voltage-gated channel, shaker-related subfamily, beta member 3
NM_004732
KCNAB3
3.66
E
-
01
1.35
Potassium voltage-gated channel, Shab-related subfamily, member 1
NM_004975
KCNB1
7.42
E
-
08
16.32
2.59
Potassium voltage-gated channel, Shab-related subfamily, member 2
NM_004770
KCNB2
1.54
E
-
05
4.58
Potassium voltage-gated channel, Shaw-related subfamily, member 1, transcript variant A
NM_001112741
KCNC1
1.47
E
-
01
1.75
Potassium voltage-gated channel, Shaw-related subfamily, member 1, transcript variant B
NM_004976
KCNC1
4.86
E
-
08
13.97
Potassium voltage-gated channel, Shaw-related subfamily, member 1, transcript variant A
NM_001112741
KCNC1
2.17
E
-
01
1.56
Potassium voltage-gated channel, Shaw-related subfamily, member 2, transcript variant 1
NM_139136
KCNC2
8.53
E
-
01
1.06
Potassium voltage-gated channel, Shaw-related subfamily, member 2, transcript variant 2
NM_139137
KCNC2
4.04
E
-
01
1.34
Potassium voltage-gated channel, Shaw-related subfamily, member 3
NM_004977
KCNC3
3.56
E
-
01
1.20
Potassium voltage-gated channel, Shaw-related subfamily, member 4, transcript variant 3
NM_001039574
KCNC4
7.70
E
-
02
−1.40
Potassium voltage-gated channel, Shal-related subfamily, member 1
NM_004979
KCND1
1.48
E
-
04
7.11
Potassium voltage-gated channel, Shal-related subfamily, member 2
NM_012281
KCND2
1.62
E
-
12
91.08
2.76
−2.57
Potassium voltage-gated channel, Shal-related subfamily, member 2
NM_012281
KCND2
2.76
E
-
09
21.83
Potassium voltage-gated channel, Shal-related subfamily, member 3 [Source: HGNC Symbol; Acc: 6239]
ENST00000369697
KCND3
5.36
E
-
01
−1.36
Potassium voltage-gated channel, Shal-related subfamily, member 3, transcript variant 1
NM_004980
KCND3
1.05
E
-
01
1.55
Potassium voltage-gated channel, Shal-related subfamily, member 3, transcript variant 1
NM_004980
KCND3
4.41
E
-
01
1.37
Potassium voltage-gated channel, Shal-related subfamily, member 3 [Source: HGNC Symbol; Acc: 6239]
ENST00000369697
KCND3
3.86
E
-
04
−1.84
Potassium voltage-gated channel, Isk-related family, member 1, transcript variant 2
NM_000219
KCNE1
3.53
E
-
01
−1.45
Potassium voltage-gated channel, Isk-related family, member 1, transcript variant 2
NM_000219
KCNE1
3.59
E
-
01
1.25
KCNE1-like
NM_012282
KCNE1L
1.34
E
-
08
4.44
−2.18
KCNE1-like
NM_012282
KCNE1L
1.11
E
-
08
3.65
KCNE1-like
NM_012282
KCNE1L
6.41
E
-
03
1.88
Potassium voltage-gated channel, Isk-related family, member 2
NM_172201
KCNE2
1.41
E
-
04
3.93
Potassium voltage-gated channel, Isk-related family, member 3
NM_005472
KCNE3
8.65
E
-
15
52.36
Potassium voltage-gated channel, Isk-related family, member 4
NM_080671
KCNE4
5.04
E
-
01
1.20
Potassium voltage-gated channel, subfamily F, member 1
NM_002236
KCNF1
2.25
E
-
05
6.48
2.84
Potassium voltage-gated channel, subfamily G, member 1
NM_002237
KCNG1
8.51
E
-
03
−1.82
Potassium voltage-gated channel, subfamily G, member 1
NM_002237
KCNG1
1.55
E
-
01
−1.65
Potassium voltage-gated channel, subfamily G, member 2
NM_012283
KCNG2
6.21
E
-
02
1.32
Potassium voltage-gated channel, subfamily G, member 3, transcript variant 1
NM_133329
KCNG3
3.74
E
-
11
58.95
−2.93
Potassium voltage-gated channel, subfamily G, member 4
NM_172347
KCNG4
3.36
E
-
03
−3.33
Potassium voltage-gated channel, subfamily G, member 4,  (cDNA clone IMAGE: 3028985)
BC008969
KCNG4
2.24
E
-
04
−3.29
Potassium voltage-gated channel, subfamily H (eag-related), member 1, transcript variant 1
NM_172362
KCNH1
8.05
E
-
01
−1.15
Potassium voltage-gated channel, subfamily H (eag-related), member 2, transcript variant 1
NM_000238
KCNH2
5.94
E
-
04
37.53
Potassium voltage-gated channel, subfamily H (eag-related), member 2, transcript variant 2
NM_172056
KCNH2
5.70
E
-
03
1.73
Potassium voltage-gated channel, subfamily H (eag-related), member 3
NM_012284
KCNH3
9.65
E
-
01
1.01
Potassium voltage-gated channel, subfamily H (eag-related), member 4
NM_012285
KCNH4
3.18
E
-
01
−1.24
Potassium voltage-gated channel, subfamily H (eag-related), member 5, transcript variant 2
NM_172376
KCNH5
3.04
E
-
03
2.96
Potassium voltage-gated channel, subfamily H (eag-related), member 5, transcript variant 1
NM_139318
KCNH5
5.41
E
-
01
1.47
Potassium voltage-gated channel, subfamily H (eag-related), member 6, transcript variant 2
NM_173092
KCNH6
2.93
E
-
02
3.04
cDNA FLJ33650 fis, clone BRAMY2024514, highly similar to Rattus norvegicus Potassium channel (erg2)
AK090969
KCNH6
2.08
E
-
05
12.42
Potassium voltage-gated channel, subfamily H (eag-related), member 6, transcript variant 2
NM_173092
KCNH6
2.55
E
-
02
2.29
Potassium voltage-gated channel, subfamily H (eag-related), member 7, transcript variant 2
NM_173162
KCNH7
4.63
E
-
01
−1.40
Potassium voltage-gated channel, subfamily H (eag-related), member 7, transcript variant 1
NM_033272
KCNH7
7.58
E
-
01
−1.09
Potassium voltage-gated channel, subfamily H (eag-related), member 8
NM_144633
KCNH8
3.00
E
-
09
24.57
2.97
Kv channel interacting protein 1, transcript variant 1
NM_001034837
KCNIP1
8.33
E
-
02
1.96
4.24
Kv channel interacting protein 2, transcript variant 7
NM_173197
KCNIP2
6.43
E
-
01
1.21
Kv channel interacting protein 2, transcript variant 1
NM_014591
KCNIP2
2.53
E
-
03
1.96
Kv channel interacting protein 3, calsenilin, transcript variant 1
NM_013434
KCNIP3
1.15
E
-
03
−3.47
Kv channel interacting protein 4, transcript variant 5
NM_001035003
KCNIP4
6.73
E
-
01
1.16
2.01
Kv channel interacting protein 4, transcript variant 5
NM_001035003
KCNIP4
9.26
E
-
01
1.05
Potassium voltage-gated channel, KQT-like subfamily, member 1, transcript variant 1
NM_000218
KCNQ1
3.31
E
-
09
79.52
Potassium voltage-gated channel, KQT-like subfamily, member 2, transcript variant 5
NM_172109
KCNQ2
5.68
E
-
19
3408.43
Potassium voltage-gated channel, KQT-like subfamily, member 2, transcript variant 3
NM_004518
KCNQ2
1.29
E
-
02
1.82
Potassium voltage-gated channel, KQT-like subfamily, member 2,  (cDNA clone IMAGE: 4154700)
BC020384
KCNQ2
1.09
E
-
08
37.12
Potassium voltage-gated channel, KQT-like subfamily, member 3, transcript variant 1
NM_004519
KCNQ3
1.10
E
-
04
−1.69
Potassium voltage-gated channel, KQT-like subfamily, member 4, transcript variant 1
NM_004700
KCNQ4
9.77
E
-
01
1.02
Potassium voltage-gated channel, KQT-like subfamily, member 5, transcript variant 1
NM_019842
KCNQ5
9.81
E
-
02
−1.79
Potassium voltage-gated channel, delayed-rectifier, subfamily S, member 1
NM_002251
KCNS1
3.39
E
-
01
−1.27
−2.64
Potassium voltage-gated channel, delayed-rectifier, subfamily S, member 2
NM_020697
KCNS2
6.19
E
-
02
−2.45
2.11
Potassium voltage-gated channel, delayed-rectifier, subfamily S, member 3
NM_002252
KCNS3
1.04
E
-
04
2.22
−2.61
−2.39
Potassium channel, subfamily T, member 1 (sodium activated)
NM_020822
KCNT1
8.51
E
-
02
−2.17
Potassium channel, subfamily V, member 1
NM_014379
KCNV1
7.84
E
-
02
1.58
Potassium channel, subfamily V, member 2
NM_133497
KCNV2
7.63
E
-
01
−1.16
(k)
Inwardly rectifying potassium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Potassium inwardly-rectifying channel, subfamily J, member 1, transcript variant rom-k5
NM_153767
KCNJ1
2.54
E
-
02
2.66
Potassium inwardly-rectifying channel, subfamily J, member 1, transcript variant rom-k5
NM_153767
KCNJ1
8.51
E
-
01
−1.05
Potassium inwardly-rectifying channel, subfamily J, member 2
NM_000891
KCNJ2
5.14
E
-
04
4.38
Potassium inwardly-rectifying channel, subfamily J, member 3
NM_002239
KCNJ3
4.56
E
-
01
1.34
Potassium inwardly-rectifying channel, subfamily J, member 4, transcript variant 1
NM_152868
KCNJ4
4.80
E
-
02
2.30
Potassium inwardly-rectifying channel, subfamily J, member 5
NM_000890
KCNJ5
1.88
E
-
08
−45.40
Potassium inwardly-rectifying channel, subfamily J, member 5
NM_000890
KCNJ5
4.42
E
-
12
−109.11
Potassium inwardly-rectifying channel, subfamily J, member 6
NM_002240
KCNJ6
3.29
E
-
05
6.75
5.54
Potassium inwardly-rectifying channel, subfamily J, member 8
NM_004982
KCNJ8
1.98
E
-
04
5.97
2.74
Potassium inwardly-rectifying channel, subfamily J, member 9 [Source: HGNC Symbol; Acc: 6270]
ENST00000368088
KCNJ9
3.17
E
-
01
1.49
Potassium inwardly-rectifying channel, subfamily J, member 9
NM_004983
KCNJ9
3.07
E
-
01
1.79
Potassium inwardly-rectifying channel, subfamily J, member 10
NM_002241
KCNJ10
8.85
E
-
04
4.14
Potassium inwardly-rectifying channel, subfamily J, member 10
NM_002241
KCNJ10
9.56
E
-
01
1.01
Potassium inwardly-rectifying channel, subfamily J, member 11, transcript variant 1
NM_000525
KCNJ11
4.00
E
-
04
2.93
Potassium inwardly-rectifying channel, subfamily J, member 12
NM_021012
KCNJ12
1.00
E
-
01
1.47
Potassium inwardly-rectifying channel, subfamily J, member 12
NM_021012
KCNJ12
3.53
E
-
06
5.81
Potassium inwardly-rectifying channel, subfamily J, member 13, transcript variant 1
NM_002242
KCNJ13
7.75
E
-
01
1.20
Potassium inwardly-rectifying channel, subfamily J, member 14, transcript variant 2
NM_170720
KCNJ14
9.05
E
-
02
−1.40
Potassium inwardly-rectifying channel, subfamily J, member 15, transcript variant 1
NM_170736
KCNJ15
3.41
E
-
08
−150.95
Potassium inwardly-rectifying channel, subfamily J, member 16, transcript variant 2
NM_170741
KCNJ16
2.22
E
-
01
−1.93
(l)
Two-P potassium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Potassium channel, subfamily K, member 1
NM_002245
KCNK1
3.02
E
-
04
−1.68
Potassium channel, subfamily K, member 2, transcript variant 1
NM_001017424
KCNK2
3.46
E
-
01
1.57
Potassium channel, subfamily K, member 3
NM_002246
KCNK3
9.98
E
-
01
1.00
2.36
Potassium channel, subfamily K, member 3
NM_002246
KCNK3
8.75
E
-
01
−1.10
Potassium channel, subfamily K, member 3
NM_002246
KCNK3
5.34
E
-
01
−1.30
Potassium channel, subfamily K, member 3 [Source: HGNC Symbol; Acc: 6278]
ENST00000302909
KCNK3
2.53
E
-
01
1.52
Potassium channel, subfamily K, member 4
NM_033310
KCNK4
6.21
E
-
01
−1.14
2.05
Potassium channel, subfamily K, member 5
NM_003740
KCNK5
1.16
E
-
14
29.46
−2.35
−2.03
Potassium channel, subfamily K, member 6
NM_004823
KCNK6
1.22
E
-
06
−3.48
−2.20
Potassium channel, subfamily K, member 6
NM_004823
KCNK6
2.05
E
-
08
−5.11
Potassium channel, subfamily K, member 6
NM_004823
KCNK6
7.04E−06
−5.22
Potassium channel, subfamily K, member 7, transcript variant A
NM_033347
KCNK7
1.17
E
-
01
−1.52
Potassium channel, subfamily K, member 9
NM_016601
KCNK9
6.67
E
-
01
−1.29
Potassium channel, subfamily K, member 10, transcript variant 1
NM_021161
KCNK10
2.63
E
-
01
−1.30
Potassium channel, subfamily K, member 10, transcript variant 2
NM_138317
KCNK10
1.41
E
-
02
1.43
Potassium channel, subfamily K, member 12
NM_022055
KCNK12
4.58
E
-
10
23.40
−5.58
Potassium channel, subfamily K, member 13
NM_022054
KCNK13
7.65
E
-
01
−1.10
Potassium channel, subfamily K, member 15
NM_022358
KCNK15
4.96
E
-
02
−1.50
Potassium channel, subfamily K, member 15
NM_022358
KCNK15
9.10
E
-
01
−1.09
Pancreatic potassium channel TALK-1d;  alternatively spliced
AY253147
KCNK16
2.17
E
-
02
−2.43
Potassium channel, subfamily K, member 17, transcript variant 1
NM_031460
KCNK17
1.87
E
-
11
28.60
Potassium channel, subfamily K, member 17, transcript variant 1
NM_031460
KCNK17
1.52
E
-
05
19.62
Potassium channel, subfamily K, member 18
NM_181840
KCNK18
1.77
E
-
01
1.61
(m)
Calcium-activated potassium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 2
NM_002247
KCNMA1
1.01
E
-
02
1.84
2.01
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 1
NM_001014797
KCNMA1
3.19
E
-
01
1.32
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 2
NM_002247
KCNMA1
3.67
E
-
03
2.27
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 2
NM_002247
KCNMA1
8.53
E
-
02
1.44
Maxi-K channel HSLO
AF349445
KCNMA1
3.04
E
-
01
1.44
Potassium large conductance calcium-activated channel, subfamily M, alpha member 1, transcript variant 2
NM_002247
KCNMA1
2.15
E
-
01
−1.23
Potassium large conductance calcium-activated channel, subfamily M, beta member 1
NM_004137
KCNMB1
7.12
E
-
02
−1.41
Potassium large conductance calcium-activated channel, subfamily M, beta member 1
NM_004137
KCNMB1
2.23
E
-
06
7.82
Potassium large conductance calcium-activated channel, subfamily M, beta member 2, transcript variant 1
NM_181361
KCNMB2
3.36
E
-
01
1.56
Potassium large conductance calcium-activated channel, subfamily M, beta member 2, transcript variant 1
NM_181361
KCNMB2
1.17
E
-
01
1.47
Potassium large conductance calcium-activated channel, subfamily M beta member 3, transcript variant 1
NM_171828
KCNMB3
1.41
E
-
05
2.63
Potassium large conductance calcium-activated channel, subfamily M, beta member 4
NM_014505
KCNMB4
8.85
E
-
12
103.99
Potassium large conductance calcium-activated channel, subfamily M, beta member 4 [Source: HGNC Symbol; Acc: 6289]
ENST00000258111
KCNMB4
9.22
E
-
10
18.40
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 1
NM_002248
KCNN1
3.40
E
-
05
4.67
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2, transcript variant 1
NM_021614
KCNN2
1.88
E
-
13
22.23
−3.63
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3, transcript variant 1
NM_002249
KCNN3
2.58
E
-
06
8.25
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3, transcript variant 3
NM_001204087
KCNN3
1.11
E
-
07
15.29
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4
NM_002250
KCNN4
1.06
E
-
02
−1.84
(n)
P2X receptors
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Purinergic receptor P2X, ligand-gated ion channel, 1
NM_002558
P2RX1
7.71
E
-
01
1.14
Purinergic receptor P2X, ligand-gated ion channel, 2, transcript variant 4
NM_170683
P2RX2
5.25
E
-
02
−1.66
Purinergic receptor P2X, ligand-gated ion channel, 3
NM_002559
P2RX3
2.43
E
-
02
−1.76
Purinergic receptor P2X, ligand-gated ion channel, 4
NM_002560
P2RX4
8.68
E
-
01
−1.03
Purinergic receptor P2X, ligand-gated ion channel, 5, transcript variant 1
NM_002561
P2RX5
7.68
E
-
08
6.97
Purinergic receptor P2X, ligand-gated ion channel, 5, transcript variant 2
NM_175080
P2RX5
6.13
E
-
02
1.54
Purinergic receptor P2X, ligand-gated ion channel, 6 [Source: HGNC Symbol; Acc: 8538]
ENST00000413302
P2RX6
4.13
E
-
01
1.68
Purinergic receptor P2X, ligand-gated ion channel, 7, transcript variant 1
NM_002562
P2RX7
6.13
E
-
01
1.23
Purinergic receptor P2X, ligand-gated ion channel, 7, transcript variant 1
NM_002562
P2RX7
9.17
E
-
01
1.04
(o)
Transient receptor potential channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Polycystic kidney disease 2 (autosomal dominant)
NM_000297
PKD2
7.48
E
-
07
1.79
Polycystic kidney disease 2 (autosomal dominant)
NM_000297
PKD2
2.38
E
-
05
1.98
Polycystic kidney disease 2-like 1
NM_016112
PKD2L1
1.29
E
-
03
4.66
Polycystic kidney disease 2-like 2
NM_014386
PKD2L2
1.94
E
-
01
1.49
Polycystic kidney disease 2-like 2
NM_014386
PKD2L2
7.43
E
-
01
1.19
Polycystic kidney disease 2-like 2
NM_014386
PKD2L2
6.74
E
-
01
1.09
Transient receptor potential cation channel, subfamily A, member 1
NM_007332
TRPA1
2.99
E
-
01
1.74
Transient receptor potential cation channel, subfamily A, member 1
NM_007332
TRPA1
5.64
E
-
02
2.70
Transient receptor potential cation channel, subfamily C, member 1
NM_003304
TRPC1
4.30
E
-
06
2.01
Transient receptor potential cation channel, subfamily C, member 3, transcript variant 2
NM_003305
TRPC3
1.12
E
-
07
5.78
2.45
Transient receptor potential cation channel, subfamily C, member 4, transcript variant alpha
NM_016179
TRPC4
3.25
E
-
07
25.38
Transient receptor potential cation channel, subfamily C, member 5
NM_012471
TRPC5
1.20
E
-
01
1.28
Transient receptor potential cation channel, subfamily C, member 6
NM_004621
TRPC6
1.21
E
-
01
2.33
Transient receptor potential cation channel, subfamily C, member 7, transcript variant 1
NM_020389
TRPC7
6.18
E
-
01
−1.36
Transient receptor potential cation channel, subfamily M, member 1
NM_002420
TRPM1
2.29
E
-
01
1.31
Transient receptor potential cation channel, subfamily M, member 2, transcript variant 1
NM_003307
TRPM2
1.22
E
-
01
1.97
Transient receptor potential cation channel, subfamily M, member 2, transcript variant 1
NM_003307
TRPM2
5.04
E
-
02
2.53
Transient receptor potential cation channel, subfamily M, member 3, transcript variant 7
NM_206948
TRPM3
3.04
E
-
09
10.69
Transient receptor potential cation channel, subfamily M, member 3 [Source: HGNCSymbol; Acc: 17992]
ENST00000354500
TRPM3
2.34
E
-
03
3.74
Transient receptor potential cation channel, subfamily M, member 3, transcript variant 7
NM_206948
TRPM3
3.41
E
-
06
6.23
Transient receptor potential cation channel, subfamily M, member 3, transcript variant 9
NM_001007471
TRPM3
7.23
E
-
01
1.13
Transient receptor potential cation channel, subfamily M, member 3, transcript variant 9
NM_001007471
TRPM3
1.54
E
-
05
2.60
Transient receptor potential cation channel, subfamily M, member 4, transcript variant 1
NM_017636
TRPM4
3.72
E
-
02
−1.89
Transient receptor potential cation channel, subfamily M, member 5
NM_014555
TRPM5
8.21
E
-
01
−1.08
Transient receptor potential cation channel, subfamily M, member 6, transcript variant a
NM_017662
TRPM6
3.80
E
-
01
1.64
Transient receptor potential cation channel, subfamily M, member 6, transcript variant a
NM_017662
TRPM6
9.10
E
-
01
1.05
Transient receptor potential cation channel, subfamily M, member 6, transcript variant a
NM_017662
TRPM6
5.32
E
-
07
5.59
Transient receptor potential cation channel, subfamily M, member 6, transcript variant a
NM_017662
TRPM6
3.32
E
-
01
1.36
Transient receptor potential cation channel, subfamily M, member 7
NM_017672
TRPM7
2.16
E
-
02
−1.25
Transient receptor potential cation channel, subfamily M, member 7
NM_017672
TRPM7
3.64
E
-
03
−1.38
Transient receptor potential cation channel, subfamily M, member 8
NM_024080
TRPM8
2.04
E
-
01
1.89
Transient receptor potential cation channel, subfamily V, member 1, transcript variant 3
NM_080706
TRPV1
3.59
E
-
05
1.92
Transient receptor potential cation channel, subfamily V, member 1, transcript variant 3
NM_080706
TRPV1
4.14
E
-
05
2.25
Transient receptor potential cation channel, subfamily V, member 2
NM_016113
TRPV2
8.02
E
-
08
4.68
Transient receptor potential cation channel, subfamily V, member 3
NM_145068
TRPV3
4.64
E
-
01
1.35
Transient receptor potential cation channel, subfamily V, member 3
NM_145068
TRPV3
1.35
E
-
01
−2.39
Transient receptor potential cation channel, subfamily V, member 4, transcript variant 2
NM_147204
TRPV4
4.33
E
-
01
1.39
Transient receptor potential cation channel, subfamily V, member 5,  (cDNA clone MGC: 34269 IMAGE: 5186668)
BC034740
TRPV5
1.00
E
-
01
1.38
Transient receptor potential cation channel, subfamily V, member 5
NM_019841
TRPV5
3.14
E
-
01
−1.40
Transient receptor potential cation channel, subfamily V, member 6
NM_018646
TRPV6
1.57
E
-
01
−1.38
(p)
Voltage-gated sodium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Sodium channel, voltage-gated, type I, alpha subunit, transcript variant 2
NM_006920
SCN1A
1.98
E
-
01
1.54
Sodium channel, voltage-gated, type I, beta, transcript variant b
NM_199037
SCN1B
9.95
E
-
01
−1.00
Sodium channel, voltage-gated, type II, alpha subunit, transcript variant 1
NM_021007
SCN2A
4.16
E
-
01
1.62
5.00
Sodium channel, voltage-gated, type II, beta
NM_004588
SCN2B
3.61
E
-
01
−1.58
Sodium channel, voltage-gated, type II, beta
NM_004588
SCN2B
8.16
E
-
04
−2.41
Sodium channel, voltage-gated, type III, alpha subunit, transcript variant 1
NM_006922
SCN3A
2.87
E
-
01
−2.00
2.85
Sodium channel, voltage-gated, type III, alpha subunit, transcript variant 1
NM_006922
SCN3A
1.89
E
-
01
1.49
Sodium channel, voltage-gated, type III, beta, transcript variant 1
NM_018400
SCN3B
8.74
E
-
01
−1.06
4.70
Sodium channel, voltage-gated, type III, beta, transcript variant 1
NM_018400
SCN3B
1.57
E
-
01
−1.46
Sodium channel, voltage-gated, type III, beta, transcript variant 1
NM_018400
SCN3B
1.56
E
-
01
1.96
Sodium channel, voltage-gated, type IV, alpha subunit
NM_000334
SCN4A
1.62
E
-
08
9.91
Sodium channel, voltage-gated, type IV, beta, transcript variant 1
NM_174934
SCN4B
3.25
E
-
04
−3.66
Sodium channel, voltage-gated, type V, alpha subunit, transcript variant 1
NM_198056
SCN5A
2.43
E
-
08
14.10
Sodium channel, voltage-gated, type V, alpha subunit, transcript variant 2
NM_000335
SCN5A
4.93
E
-
02
1.95
Sodium channel, voltage-gated, type VII, alpha
NM_002976
SCN7A
4.49
E
-
03
1.63
Sodium channel, voltage-gated, type VII, alpha
NM_002976
SCN7A
2.07
E
-
01
1.72
Sodium channel, voltage gated, type VIII, alpha subunit, transcript variant 1
NM_014191
SCN8A
1.89
E
-
09
15.61
Sodium channel, voltage gated, type VIII, alpha subunit, transcript variant 1
NM_014191
SCN8A
4.06
E
-
07
11.23
Sodium channel, voltage-gated, type IX, alpha subunit
NM_002977
SCN9A
4.08
E
-
08
11.51
Sodium channel, voltage-gated, type IX, alpha subunit
NM_002977
SCN9A
1.62
E
-
01
1.66
Sodium channel, voltage-gated, type IX, alpha subunit
NM_002977
SCN9A
3.38
E
-
03
2.57
Sodium channel, voltage-gated, type X, alpha subunit
NM_006514
SCN10A
4.06
E
-
01
1.35
Sodium channel, voltage-gated, type XI, alpha subunit
NM_014139
SCN11A
3.02
E
-
01
1.57
Sodium channel, voltage-gated, type XI, alpha subunit [Source: HGNC Symbol; Acc: 10583]
ENST00000444237
SCN11A
8.83
E
-
03
1.94
(q)
Nonvoltage-gated sodium channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Sodium channel, nonvoltage-gated 1 alpha, transcript variant 1
NM_001038
SCNN1A
1.33
E
-
09
51.49
−21.13
−10.71
Sodium channel, nonvoltage-gated 1, beta
NM_000336
SCNN1B
2.11
E
-
01
1.64
Sodium channel, nonvoltage-gated 1, beta
NM_000336
SCNN1B
5.52
E
-
01
1.09
Sodium channel, nonvoltage-gated 1, delta, transcript variant 1
NM_001130413
SCNN1D
8.43
E
-
02
1.49
Sodium channel, nonvoltage-gated 1, gamma
NM_001039
SCNN1G
2.33
E
-
01
1.59
Gamma subunit of epithelial amiloride-sensitive sodium channel
X87160
SCNN1G
3.99
E
-
01
1.27
(r)
Two-pore channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Two-pore segment channel 1, transcript variant 1
NM_001143819
TPCN1
6.20
E
-
04
−1.76
Two-pore segment channel 1, transcript variant 2
NM_017901
TPCN1
1.71
E
-
03
−2.10
Two-pore segment channel 1, transcript variant 2
NM_017901
TPCN1
3.55
E
-
04
−2.44
Two-pore segment channel 1, transcript variant 1
NM_001143819
TPCN1
8.06
E
-
03
−1.83
Two-pore segment channel 2
NM_139075
TPCN2
5.06
E
-
01
−1.15
(s)
Zinc-activated ligand-gated ion channels
Gene name
Accession number
Gene symbol
P
Fold changeKer → hiPSC
Fold changehiPSC → Neuron
Fold change hiPSC → CM
Zinc-activated ligand-gated ion channel
NM_180990
ZACN
9.24
E
-
02
1.45


## 3.2. Voltage-Gated Calcium Channels

Voltage-gated calcium channels are crucially involved in the Ca2+-influx thereby playing an important role in calcium signaling of virtually all cells. High-voltage-gated calcium channels include the neural N-type channel, the poorly defined brain-specific R-type channel, the closely related P/Q-type channel, and the dihydropyridine-sensitive L-type channels responsible for excitation-contraction coupling of skeletal, smooth, and cardiac muscles as well as for hormone secretion in endocrine cells (reviewed in [24]). While mainly permeable for calcium ions they also show a low permeability for sodium ions. Upon depolarization of the cell they mediate a calcium influx into the cell. The channels consist of the main alpha subunit as well as regulatory beta, alpha 2/delta, and gamma subunits. The α1 subunit forms the ion conducting pore while the associated subunits have several functions including modulation of gating [25].CACNA1A mutations are for example involved in ataxia [26]. We have analyzed their expression with 42 probes. During reprogramming 14 (33%) of them are significantly upregulated while only 1 (2%) is significantly downregulated. From iPSCs to neurons, as expected, neuronal alpha-subunits CACNA1D, CACNA1Eareupregulated together with several neuronal channel subunits (α2δ, β, and γ). In cardiomyocytes, solely the alpha subunit of the cardiac CACNA1Cis upregulated. Of note, none of the differentiated progeny downregulated any voltage-gated calcium channels.


## 3.3. Sperm-Associated Cation Channels

Sperm-associated cation channels or CatSper channels are calcium ion channels. They are flagellar proteins involved in sperm motility and therefore affect fertility [27]. During reprogramming to iPSCs, from seven used probes just one showed a significant downregulation and none had a significant upregulation. We observed nothing noteworthy in the differentiated progeny.


## 3.4. Nicotinic Acetylcholine Receptors

Nicotinic acetylcholine receptors play a role in interneuronal synapses and neuromuscular junctions. They are composed of five subunits as homomeric or heteromeric receptors. They are located at the postsynaptic site and upon binding of acetylcholine they allow the transmission of cations, especially sodium and potassium ions, in some versions also calcium ions. This leads to a depolarization of the membrane and triggers further signaling pathways [28]. Several acetylcholine receptors and subunits are thought to play roles in a variety of pathomechanisms, for example, psychiatric disorders, cardiovascular diseases, or cancer [29–31]. From 21 probes, 5 (24%) showed a significant upregulation while 3 (14%) showed a significant downregulation from keratinocytes to iPSCs. In neurons, solely the neuronal nicotinic acetylcholine receptor CHRNA6 alpha subunit was upregulated, none in cardiomyocytes.


## 3.5. Cyclic Nucleotide-Gated Channels

Cyclic nucleotide-gated channels form tetrameric channels which—upon binding of cGMP—allow a flow of cations. For that, these channels track the intracellular concentration of cNMPs to produce a voltage response [32]. Their major role is the depolarization of rod photoreceptors, but they are also found in other tissues like olfactory sensory neurons [33], testis, kidney, or heart [34] and play a role in cellular development such as neuronal growth cone guidance [35]. Defects in these genes are reported to cause retinitis pigmentosa [36]. From 7 used probes one showed a significant upregulation and one showed a significant downregulation (both 14%) during reprogramming, while none was differentially regulated in differentiated neurons or cardiomyocytes.


## 3.6. GABA Receptors

GABA (gamma-aminobutyric acid) receptors are ligand-gated chloride channels. Since GABA is the main inhibitory neurotransmitter in the central nervous system GABA receptors play an important role for the brain function. The receptors are composed of five subunits which form heteromers. The GABA receptors are a drug target for anesthetics and other psychoactive drugs. We have analyzed 29 probes within GABA receptor subunits. From keratinocytes to iPSCs, 6 (21%) of them are significantly upregulated while just one (3%) is significantly downregulated. Interestingly, none was up- or downregulated in differentiated neurons, whileGABRB3 was downregulated  and GABRP was upregulated in cardiomyocytes. Up to now, more or less nothing is known about GABA receptors or their subunits in cardiac cells.


## 3.7. Glycine Receptors

Glycine receptors are inhibitory receptors of the postsynaptic site. They are activated by glycine and mediate an influx of chloride ions. Accordingly, GlyRs regulate not only the excitability of motor and sensory neurons but are also essential for the processing of photoreceptor signals, neuronal development, and inflammatory pain sensitization [37]. The heteromeric pore is formed by five subunits. Concerning their role in pathomechanisms, it was reported that mutations are causing hyperekplexia (also known as startle disease) [38]. We have analyzed 7 probes and none of them was significantly altered in hiPSCs. Transcript levels for the alpha2 subunit and the beta subunit were highly upregulated in differentiated neurons, pointing to their functional role in the nervous system.


## 3.8. Ionotropic Glutamate Receptors

Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Therefore, ionotropic glutamate receptors play a key role for learning and memory processes. They are located in the postsynaptic membrane and are composed of several heteromeric subunits. Ionotropic glutamate receptors are further divided into AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate), NMDA (N-Methyl-D-aspartate) or kainate receptors depending on their sensitivity for the agonists. From 36 probes, 5 (14%) showed a significantly increased expression and 2 (6%) showed a decreased expression in iPSCs compared to keratinocytes. As expected, several subunits were upregulated in neurons (none downregulated). None was upregulated in cardiomyocytes, while the kainate subtypeGRIK5 was downregulated.


## 3.9. Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels

Hyperpolarization-activated cyclic nucleotide-gated channels are homodimers or heterodimers and form a hyperpolarization-activated potassium channel. CNG channels display a very complex heteromeric structure with various subunits and domains that play a critical role in their function [39]. They contribute to pacemaker currents in the heart [40] but are also found in neurons [41]. We have analyzed 5 probes and 3 (60%) of them showed a significant upregulation while none was downregulated after reprogramming. In neurons the HCN3 channel transcript was upregulated, which plays a role in several neuronal functions including excitability of basal ganglia output neurons [42]. Although HCN4 for example plays a critical role in the conduction system of the heart, we did not observe a specific regulation in cardiomyocytes.


## 3.10. Serotonin Receptors

Serotonin (or 5-hydroxytryptamine) receptors are ligand-gated receptors mainly found presynaptically in neurons. The type 3 receptor is the only ion channel while the other serotonin receptors are G-protein-coupled receptors. It forms a heteropentameric pore which upon activation by serotonin allows the flow of sodium and potassium, leading to a depolarization. Serotonin receptors modulate neuronal function and are therefore involved in various brain functions. The analysis of 6 probes for type 3 serotonin receptors showed a significant upregulation of 2 (33%, both forHTR3A) probes while none was downregulated in hiPSCs. Although we expected serotonin receptors to be upregulated during neuronal differentiation, no subunit was upregulated in neurons or cardiomyocytes, while only the receptor transcript for HTR3Awas downregulated in neurons.


## 3.11. Voltage-Gated Potassium Channels

Voltage-gated potassium channels are composed of a large group of subunits with different characteristics concerning for example their inactivation speed. Functional channels are formed by heterotetramers. The channels are highly specific for potassium with a low affinity for sodium or other cations. Voltage-gated potassium channels are responsible for the repolarization of excitable cells following the sodium-mediated excitation of an action potential and are therefore found in neurons and other cells displaying action potentials. We have analyzed 81 probes. From keratinocytes to hiPSCs, 25 (31%) were significantly upregulated while only 3 (4%) were significantly downregulated. In neurons, several subunits were upregulated includingKCNB1, coding for Kv2.1 and KCND2, both are better known for their role in cardiac cell excitability as well as KCNF1, KCNH8, and KCNIP1, all known for their contribution in neuronal excitability [43]. It should be noted that KCNT1 is actually sodium activated but is included in the alphabetical list for a better overview. Further, several “S” subunits were upregulated (KCNS2 in neurons) or downregulated (KCNS3 in neurons; KCNS1 and 3 in cardiomyocytes). These subunits are unable to form functional channels as homotetramers but instead heterotetramerize with other alpha-subunits to form conductive channels. These subunits are involved in modifying the channels response and conductivity [44]. Few is known about distinct roles in other tissues, but they were associated with for example, pain modulation [45] or airway responsiveness [46].


## 3.12. Inwardly Rectifying Potassium Channels

Inwardly rectifying potassium channels have a higher tendency to allow the flow of potassium ions into the cell rather than to the outside of the cell. Therefore, they play an important role in the maintenance of the resting membrane potential. Their activation is constitutive or controlled by ATP binding and G-proteins [47]. Functional channels are formed as homo- or heterotetramers. These channels can be found predominantly in neurons, cardiac myocytes, the pancreas, or the kidneys. From 20 analyzed probes in hiPSCs compared to keratinocytes, 8 (40%) showed a significant upregulation and 3 (15%) were significantly downregulated. The GIRK2 channel encoded by KCNJ6 is upregulated in neurons playing multiple roles in various tissues including the  pancreas and brain [48, 49] and is associated with epileptic seizures in mice lacking the gene [50]. On the other hand, Kir6.1, encoded by KCNJ8, is upregulated in cardiomyocytes and has been reported to be involved in the pathogenesis of cardiac arrest in the early repolarization syndrome [51].


## 3.13. Two-P Potassium Channels

Two-P potassium channels contain two pore-forming P domains. After dimerization they form an outward rectifying potassium channel. They can be found in several tissues and are activated by various chemical or physical means (TRAAK channels). We have analyzed 23 probes. 4 (17%) of them were significantly upregulated while 4 (17%) were significantly downregulated. In neuronsKCNK3, vital for setting the resting membrane potential and primary target for volatile anesthetics [52] as well as KCNK4,which is mechanically gated and contributes to axonal pathfinding, growth cone motility, and neurite elongation, as well as possibly having a role in touch or pain detection [53, 54], were upregulated. KCNK5 and 6 were downregulated. In cardiomyocytes, downregulation of KCNK5 and 12 was observed.


## 3.14. Calcium-Activated Potassium Channels

Calcium-activated potassium channels are mostly activated by intracellular calcium; some family members are also voltage gated. The family consists of large, intermediate, and small conductance family members. Channels are formed by two units (KCNM family) or most commonly four units (KCNN family). They are involved in, for example, afterhyperpolarization following the action potential and are predominantly found in neurons. Additionally, they are known to play different roles in cellular mechanisms, including stem cell biology [4–6, 55]. We have analyzed 18 probes of which 9 (50%) were significantly upregulated and none was significantly downregulated after reprogramming. In neurons, solely KCNN2 was downregulated, while in cardiomyocytes KCNMA1, encoding the large conductance BK-channel, involved in heart rate regulation [56], was upregulated.


## 3.15. P2X Receptors

P2X receptors are receptors for extracellular ATP and upon activation open a channel for ions, predominantly calcium. The channel is formed by homo- or heterotrimers. They are found in several tissues, mainly in the nervous system and muscle tissue. They are involved in a range of physiological processes such as modulation of synaptic transmission, vascular tone, cardiac rhythm, and contractility and immune response [57–61]. In stem cells an influence of P2X receptors on embryonic stem cell proliferation was reported [62]. From the 9 analyzed probes 1 (11%) was significantly upregulated and none downregulated. None of these receptors/channels was regulated in differentiated progeny.


## 3.16. Transient Receptor Potential Channels

Transient receptor potential channels (TRP channels) are nonselective cation channels. They show different preferences for cations, as well as different activation mechanisms and functions. TRP channels are broadly expressed throughout the organism and mediate multiple functions. These include amongst others sensor activity for a wide range of hypertrophic stimuli and mutations inTRPM4 are now recognized as causes of human cardiac conduction disorders (reviewed in [63]). Furthermore, TRP channels are related to the onset or progression of several diseases, and defects in the genes encoding TRP channels (so-called “TRP channelopathies”) underlie certain neurodegenerative disorders due to their abnormal Ca2+ signaling properties (reviewed in [64]). Additionally, TRP channels influence stem cell differentiation and survival [65, 66] and are involved in neuronal-stem-cell-derived development [67]. We have analyzed 40 probes. After reprogramming, 11 (28%) of them were significantly upregulated and none was significantly downregulated. In neurons, none of these channels was noteworthily regulated while solely TRPC3 was upregulated in cardiomyocytes, reported to be involved in conduction disturbances induced by adenosine receptor A1AR by enhanced  Ca2+ entry through the TRPC3 channel [68].


## 3.17. Voltage-Gated Sodium Channels

Voltage-gated sodium channels consist of a main alpha unit and some optional modulating or regulatory subunits. They are highly selective for sodium and are involved in a variety of cellular functions including action potential formation [69]. From 24 probes we have analyzed, 6 (25%) were significantly upregulated and two (8%) were significantly downregulated from keratinocytes to iPS cells. These channels seem to be expressed in different kinds of stem cells and during development [70–72]. It was further reported that, for example, SCN5A, highly upregulated in iPS cells, is involved in cancer stem cell invasion [73]. SCN2A, SCN3A, and SCN3Bwere upregulated in neurons, described to be involved in neuronal excitation and epilepsy pathogenesis [74]. Although voltage-gated sodium channels play multiple roles also in the cardiac system [70, 75, 76], we observed no changes of this channel family in cardiomyocytes.


## 3.18. Nonvoltage-Gated Sodium Channels

Epithelial nonvoltage-gated sodium channels are amiloride sensitive. They form heterotrimers and are involved in ion and fluid transport across epithelia in several organs. We have analyzed 6 probes and one (17%) of them was significantly upregulated while none was significantly downregulated. Interestingly, the upregulatedSCNN1A in iPS cells was subsequently downregulated both in neurons and cardiomyocytes, pointing to a possible function in stem cells. Of note, it was shown already that repression of pluripotency by retinoic acid represses the SCNN1A gene together with several other pluripotency factors [77].


## 3.19. Two-Pore Channels

Two-pore channels are cation-selective ion channels activated by the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). Upon activation calcium is released from intracellular stores [78]. We have analyzed 5 probes and while none of them was significantly upregulated two (40%) were significantly downregulated from keratinocytes to iPS cells. None of these channels was regulated in neurons or cardiomyocytes.


## 3.20. Zinc-Activated Ligand-Gated Ion Channels

The zinc-activated ligand-gated ion channel is activated upon binding of zinc. Until now just one family member is known that is expressed in several tissues [79]. Its exact function is not known. The expression was not significantly altered as shown by one probe in all cells.


## 4. Discussion

Although ion channels are mainly known for their role in electrically excitable cells they can be found in almost all tissues and are additionally involved in various processes such as cell differentiation and maturation [3, 4, 6, 12, 24, 47, 70]. These large groups of channel proteins are still underestimated concerning their role during embryonic development and cell fate determination. One of the most interesting in vitro models for the elucidation of both developmental processes and disease-specific cellular impairments is represented by pluripotent stem cells. Therefore we were interested in the set of ion channels expressed in hiPSCs after reprogramming and compared this set with iPSC-derived differentiated progeny, namely, neurons and cardiomyocytes. As little is known about ion channels in hiPSCs we aimed to start the analysis with gene expression microarray data. For a comparison, we chose the cells from which they were produced—namely, keratinocytes—as the reference cell type. The comparison of 6 keratinocyte samples with 9 hiPSC samples should minimize the often observed variances between hiPSC lines. We found out that almost a third (32%) of the ion channel probes we investigated showed a significant change in gene expression. Of note, this was mostly an upregulation. Additionally, while many ion channel genes were not expressed in keratinocytes they were present in hiPSCs. This indicates that several of the analyzed channel groups might play unknown roles in stem cell biology, for example, homeostasis, proliferation, or differentiation. Interestingly, after differentiation into neurons or cardiomyocytes, relatively small groups were subsequently regulated. This includes ion channel transcripts playing important roles in the respective tissues. Nevertheless, we compared already published sets of data from different experimental setups and additionally limited the analysis to a strong fold regulation. This might lead to high dropout rates of regulated genes during measurement. Still, various channel transcripts were “logically” up- or downregulated during differentiation into neurons or cardiomyocytes, following embryonic development. iPS cells and especially patient-specific iPS cells from persons suffering from genetic mutations leading to hereditary syndromes are a very valuable tool to investigate pathogenetic mechanisms and disease associated molecular and cellular changes [80–82]. As various channel subtypes are involved in multiple pathogenetic mechanisms it would be further interesting to analyze channel transcript regulation in patient specific iPS cells and their differentiated progeny to elucidate possible disease-specific pathways.Concerning the presented study it is clear that gene regulations on transcript level do not explicitly mimic either protein levels and posttranslational modifications or protein activity. This set of data is sought to describe a global overview on transcript regulation of ion channels during distinct steps of development. It should be noted that in cases where several probes bind within one gene they do not indicate the same upregulation. Sometimes they show the same trend but miss significance, but for some cases there are considerable differences. This could hint for some yet unknown splicing variants. More detailed studies of these hypothesized splice variants could give insights into their function and broaden the still scarce knowledge.This work is intended to be a guide and start point for future work focusing on single channels and their composition, localization, and function in hiPSCs and their differentiated progeny. These studies could lead to betterin vitro differentiation protocols but also explain some of the many disease pathomechanisms related to mutations in ion channel genes.



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