Source: http://tcdb.org/tcfamilybrowse.php?tc=1.A.4
Timestamp: 2019-04-19 06:16:15+00:00

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TRP (transient receptor potential) channels represent a superfamily of cation channels conserved from worms to humans (Vennekens et al. 2012). They comprise seven subfamilies (TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, and TRPML). According to Latorre et al. (2009), TRP channels can be grouped into seven subfamilies based on their amino acid sequence homology: (1) the canonical or classic TRPs, (2) the vanilloid receptor TRPs, (3) the melastatin or long TRPs, (4) ankyrin (whose only member is the transmembrane protein 1 [TRPA1]), (5) TRPN after the nonmechanoreceptor potential C (nonpC), and the more distant cousins, the (6) polycystins and (7) mucolipins. Members of the VIC (1.A.1), RIR-CaC (2.A.3) and TRP-CC (1.A.4) Families have similar transmembrane domain structures, but very different cytosolic doman structures (Mio et al. 2008). Because of their role as cellular sensors, polymodal activation and gating properties, many TRP channels are activated by a variety of different stimuli and function as signal integrators (Latorre et al., 2009; Montell, 2005; Ramsey et al., 2006). These mammalian proteins have been tabulated revealing their accepted designations, activators and inhibitors, putative interacting proteins and proposed functions (Clapham, 2007). The founding members of the TRP superfamily are the TRPC (TRP canonical) channels, which can be activated following the stimulation of phospholipase C and/or depletion of internal calcium stores (Montell, 2005). TRPC channels regulate nicotine-dependent behavior (Feng et al., 2006). The intrinsic assembly domains that assure tetrameric TRP channel formation have been reviewed (Schindl and Romanin 2007). They also function by depolarising the membrane potential, which triggers the activation of voltage-gated Ca2+ channels.
Alonso-Carbajo et al. 2017 reviewed the functions of these proteins in human vascular smooth muscle and cardiac striated muscle. The mammalian TRP superfamily includes at least 22 genes grouped into three major subfamilies based on sequence homology: TRPV (vanilloid), TRPC (canonical), and TRPM (melastatin). Three additional subfamilies (the 'distant TRPs'), TRPP (polycystin), TRPML (mucolipin), and TRPA bring the total number of TRP-related proteins to around 30. TRP proteins are six transmembrane-domain polypeptide subunits, and four subunits assemble in the plasma membrane to form functional channels. All TRP channels are cation permeable, and most are not selective for monovalent or divalent ions. However, TRPV5 and TRPV6, display specificity for Ca2+ ions, and TRPM4 and TRPM5 are highly selective for monovalent cations and impermeant to Ca2+. TRP channels are activated by stimuli including changes in pressure, temperature, osmolarity, and intracellular Ca2+. Fatty acids and receptor-dependent vasoconstrictor agonists also activate vascular TRP channels. Most channels assemble from four identical TRP subunits, but when multiple TRP subunits are coexpressed, heteromeric channels can form (Alonso-Carbajo et al. 2017). Several of these proteins have been solved by cryo-EM (Madej and Ziegler 2018).
The mammalian TRPM gene family can be subdivided into distinct categories of cation channels that are either highly permeable for Ca2+ (TRPM3/6/7), nonselective (TRPM2/8), or Ca2+ impermeable (TRPM4/5). TRPM6/7 are fused to alpha-kinase domains, whereas TRPM2 is linked to an ADP-ribose phosphohydrolase (Nudix domain). Phylogenetic evidence suggests that Nudix-linked channels represent an ancestral type of TRPM that is present in various phyla, ranging from protists to humans (Mederos y Schnitzler et al., 2008). The pore-forming segments of invertebrate TRPM2-like proteins display high sequence similarity to those of Ca2+-selective TRPMs. Restoration of only two 'ancient' pore residues in human TRPM2 (Q981E/P983Y) increased (4-fold) its permeability for Ca2+. Conversely, introduction of a 'modern' sequence motif into mouse TRPM7 (E1047Q/Y1049P) resulted in the loss of Ca2+ permeation and a linear TRPM2-like current-voltage relationship (Mederos y Schnitzler et al., 2008).
The TRP-CC family includes a variety of channel/sensors that respond to temperature, touch, pain, osmolarity, pheromones, taste, and other stimuli (Clapham, 2003). It has also been called the store-operated calcium channel (SOC) family. These proteins are the prinicipal components in mechanosensitive channels in vertebrate hair cells (TRPA1; 1.A.4.6.1) and stretch-activated channels in various vertebrate cell types (TRPC1; 1.A.4.1.3) (Barritt and Rychkov, 2005). TRPA1 and TRPC1 may use different mechanisms of activation. (a) The functional TRPA1 channel is probably a tetramer that is composed of four identical TRPA1 polypeptide chains or a mixture of TRPA1 and another channel polypeptide. Each TRPA1 polypeptide has 17 ankyrin repeats at the cytoplasmic amino terminus. It is proposed that these are coupled to motor proteins or other regulatory proteins on the cytoplasmic face of the plasma membrane (Barritt and Rychkov, 2005). In response to the deflection of the mechanosensitive cilia bundle induced by sound, tension on the ankyrin repeat domains or changes in protein-protein interactions are altered and the channel opens to admit Ca2+ and other cations. (b) The functional TRPC1 channel is probably a tetramer that is composed of four identical TRPC1 polypeptides or a mixture of TRPC1 polypeptides and another polypeptide. Although each TRPC1 polypeptide contains 3 or 4 ankyrin domains at the N terminus, it is proposed that these are not directly involved in channel gating. In response to a stimulus, such as stretching of the membrane by an increase in the volume of the cell, the channel opens and admits Ca2+. It is possible that release of Ca2+ from the endoplasmic reticulum that is induced by thapsigargin also acts as a stimulus, which alters cell volume and therefore can activate TRPC1 through changes in tension of the phospholipid bilayer. The activation of TRP channels by polyunsaturated fatty acids has been examined, and residues involved have been identified (Riehle et al. 2018).
Prototypical members of the TRP-CC family include the Drosophila retinal proteins TRP and TRPL (Montell and Rubin, 1989; Hardie and Minke, 1993). The 81 aas integral membrane INAF-B protein forms a complex with TRP channels, and they stabilize each other (Cheng and Nash, 2007). SOC members of the family mediate the entry of extracellular Ca2+ into cells in response to depletion of intracellular Ca2+ stores (Clapham, 1996) and agonist stimulated production of inositol-1,4,5 trisphosphate (IP3). One member of the TRP-CC family, mammalian Htrp3, has been shown to form a tight complex with the IP3 receptor (TC #1.A.3.2.1). This interaction is apparently required for IP3 to stimulate Ca2+ release via Htrp3. The vanilloid receptor subtype 1 (VR1), which is the receptor for capsaicin (the 'hot' ingredient in chili peppers) and serves as a heat-activated ion channel in the pain pathway (Caterina et al., 1997), is also a member of this family, and is activated by cannabinoids (i.e., anandamide) and certain inflammatory metabolites of arachidonate such as prostaglandin E2 (Olah et al., 2001). The stretch-inhibitable non-selective cation channel (SIC) is identical to the vanilloid receptor throughout all of its first 700 residues, but it exhibits a different sequence in its last 100 residues. VR1 and SIC transport monovalent cations as well as Ca2+. VR1 is about 10x more permeable to Ca2+ than to monovalent ions. Ca2+ overload probably causes cell death after chronic exposure to capsaicin (McCleskey and Gold, 1999).
The proteins of the TRP-CC family exhibit the same topological organization with a probable KscA-type 3-dimensional structure (Dodier et al., 2004; Dohke et al., 2004). They consist of about 700-800 (VR1, SIC or ECaC) or 1300 (TRP proteins) amino acyl residues with six transmembrane spanners (TMSs) as well as a short hydrophobic 'loop' region between TMSs 5 and 6. This loop region may dip into the membrane and contribute to the ion permeation pathway (Hardie and Minke, 1993). An aspartate residue in the P-loop may form a ring of negative charges that modulate pore properties including ion selectivity and inhibitory characteristics (García-Martínez et al., 2000). VR1 forms homotetramers. In these respects, members of the TRP-CC family resemble those of the VIC family. When one member of the TRP-CC family, the IGF-regulated Ca2+ channel of Mus musculus (TC #1.A.4.2.4), was PSI-BLASTED, it retrieved a partial sequence of a Zea mays K+ channel protein (887 aas; gbY07632) that is clearly a member of the VIC family. The two homologous protein segments of 150 residues were 28% identical, 42% similar with a PSI-BLAST score (without iterations) of 2e6. This observation further suggests a common origin for certain domains in the TRP-CC and VIC families.
All members of the vanilloid family of TRP channels (TRPV) possess an N-terminal ankyrin repeat domain (ARD), which regulates calcium uptake and homeostasis. It is essential for channel assembly and regulation. The 1.7 Å crystal structure of the TRPV6-ARD revealed conserved structural elements unique to the ARDs of TRPV proteins. First, a large twist between the fourth and fifth repeats is induced by residues conserved in all TRPV ARDs. Second, the third finger loop is the most variable region in sequence, length and conformation. In TRPV6, a number of putative regulatory phosphorylation sites map to the base of this third finger. The TRPV6-ARD does not assemble as a tetramer and is monomeric in solution (Phelps et al., 2008). Voltage sensing in thermo-TRP channels has been reviewed by Brauchi et al. (Brauchi and Orio, 2011).
The transient receptor potential (TRP) family of ion channels participate in many signaling pathways. TRPV1 functions as a molecular integrator of noxious stimuli, including heat, low pH, and chemical ligands. The 19-A structure of TRPV1 determined by using single-particle electron cryomicroscopy exhibits fourfold symmetry and comprises two distinct regions: a large open basket-like domain, likely corresponding to the cytoplasmic N- and C-terminal portions, and a more compact domain, corresponding to the transmembrane portion (Moiseenkova et al., 2008). The assignment of transmembrane and cytoplasmic regions was supported by fitting crystal structures of the structurally homologous Kv1.2 channel and isolated TRPV1 ankyrin repeats into the TRPV1 structure.
Most local anaesthetics used clinically are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane. These anaesthetics block sodium channels and the excitability of neurons. Binshtok et al. (2007) tested the possibility that the excitability of primary sensory nociceptor (pain-sensing) neurons could be blocked by introducing the charged, membrane-impermeant lidocaine derivative QX-314 through the pore of the noxious-heat-sensitive TRPV1 channel (TC #1.A.4.2.1). They found that charged sodium-channel blockers can be targeted into nociceptors by the application of TRPV1 agonists to produce a pain-specific local anaesthesia. QX-314 applied externally had no effect on the activity of sodium channels in small sensory neurons when applied alone, but when applied in the presence of the TRPV1 agonist capsaicin, QX-314 blocked sodium channels and inhibited excitability (Binshtok et al., 2007).
The amino termini of TRP-CC proteins normally contain a proline-rich region and one or more ankyrin domains. VR1, for example, exhibits three such repeat domains in its amino terminal hydrophilic segment (432 amino acids). It also has a hydrophilic C-terminus that lacks recognizable motifs. The sequence similarity between VR1 and other TRP-CC family proteins is within and adjacent to the sixth TMS, including the hydrophobic 'loop' region. Unlike other TRP-CC family members, VR1 is not a SOC. Mammals appear to have multiple VR1 homologues.
One member of the TRP-CC family, TRP-PLIK (1862 aas; AF346629), has been implicated in the regulation of cell division. It has an N-terminal TRP-CC-like sequence and a C-terminal protein kinase-like sequence. It was shown to autophosphorylate and exhibits an ATP phosphorylation-dependent, non-selective, Ca2+-permeable, outward rectifying conductance (Runnels et al., 2001). Another long homologue, Melastatin, is associated with melanocytic tumor progression whereas another homologue, MTR1, is associated with Beckwith-Wiedemann syndrome and a predisposition for neoplasia. Each of these proteins may be present in the cell as several splice variants.
The rabbit kidney epithelial Ca2+ channel, ECaC, is a Ca2+-selective cation channel with monovalent cation transport activity sensitive to strong inhibition by low concentrations of Ca2+ or Mg2+. ECaC is >100 x more permeable to Ca2+ than Na+. Mutation of D542 to alanine (D542A) (not present in the TRP-CC homologue) abolishes Ca2+ permeation and divalent cation inhibition of monovalent cation permeation. The mutation does not inhibit the latter transport activity. The D542K mutation generates a nonfunctional channel. Thus, a single residue determines the characteristic cation selectivity of ECaC.
The ability to detect variations in humidity is critical for many animals. Birds, reptiles and insects all show preferences for specific humidities that influence their mating, reproduction and geographic distribution. Because of their large surface area to volume ratio, insects are particularly sensitive to humidity, and its detection can influence their survival. Two types of hygroreceptors exist in insects: one responds to an increase (moist receptor) and the other to a reduction (dry receptor) in humidity. Although previous data indicated that mechanosensation might contribute to hygrosensation, the cellular basis of hygrosensation and the genes involved in detecting humidity remain unknown. To understand better the molecular bases of humidity sensing,(Liu et al., 2007b) investigated several genes encoding channels associated with mechanosensation, thermosensing or water transport. They identified two Drosophila melanogaster transient receptor potential channels needed for sensing humidity: CG31284, named water witch (wtrw), which is required to detect moist air, and nanchung (nan), which is involved in detecting dry air. Neurons associated with specialized sensory hairs in the third segment of the antenna express these channels. Neurons expressing wtrw and nan project to central nervous system regions associated with mechanosensation (Liu et al., 2007b). The six TRP channels of dinoflagelates do not appear to be mechanoreceptors but rather are components of a mechanotransduction signaling pathway and may be activated via a PLC-dependent mechanism (Lindström et al. 2017).
TRP channels are calcium-permeable nonselective cation channels with six TMS domains and a putative pore loop between TMSs 5 and 6 (Hu et al., 2012). About 28 mammalian TRP channels have been identified, with different numbers of splicing variants for each channel gene. TRP channels have been classified into six different subgroups, including TRPV (1-6), TRPM (1-8), TRPC (1-7), TRPA1, TRPP (1-3), and TRPML (1-3), according to their sequence similarities. In general, TRP channels are involved in calcium handling (e.g., intracellular calcium mobilization and calcium reabsorption) and a broad range of sensory modalities, including pain, temperature, taste, etc. TRP channelopathies are part of important mechanisms in a variety of diseases such as neurodegenerative disorders, diabetes mellitus, inflammatory bowel diseases, epilepsy, cancer, etc. Several members of the TRP family, TRPV1-4, TRPM8, and TRPA1, also called 'ThermoTRPs,' are involved in the detection of temperature changes, thus acting as the molecular thermometers of our body. They are also polymodal nociceptors that integrate painful stimuli such as noxious temperatures and chemical insults. For example, the TRPV1 channel mediates thermal hyperalgesia and pain induced by capsaicin and acid. TRPA1 is a nociceptor that integrates many noxious environmental stimuli including oxidants and electrophilic agents. Gene deletion animals have been created to study the role of TRP channels in pain and nociception; involvement of TRPV1, TRPV3, TRPV4, and TRPA1 in nociception has been confirmed (Hu et al., 2012).
A class of ion channels that belongs to the transient receptor potential (TRP) superfamily and is present in specialized neurons are temperature detectors. These channels are classified into subfamilies, namely canonical (TRPC), melastatin (TRPM), ankyrin (TRPA), and vanilloid (TRPV). Some of these channels are activated by heat (TRPM2/4/5, TRPV1-4), while others by cold (TRPA1, TRPC5, and TRPM8) (Baez et al. 2014). These channels resemble voltage-dependent K+ channels, with their subunits containing six transmembrane segments that form tetramers. Thermal TRP channels are polymodal receptors that can be activated by temperature, voltage, pH, lipids, and agonists. Their high temperature sensitivity is due to a large enthalpy change ( approximately 100 kcal/mol), which is about five times the enthalpy change in voltage-dependent gating.
TRPV cation channels are polymodal sensors involved in a variety of physiological processes. TRPV2 is regulated by temperature, ligands such as probenecid and cannabinoids, and lipids. It may play a role in somatosensation, osmosensation and innate immunity. Zubcevic et al. 2016 presented the atomic model of rabbit TRPV2 in its putative desensitized state, as determined by cryo-EM at 4 A resolution. TMS6 (S6), which is involved in gate opening, adopts a conformation different from the one observed in TRPV1. Structural comparisons of TRPV1 and TRPV2 indicate that a rotation of the ankyrin-repeat domain is coupled to pore opening via the TRP domain, and this pore opening can be modulated by rearrangements in the secondary structure of S6.
Plasma membrane ion channels, and in particular TRPC channels, need a specific membrane environment and association with scaffolding, signaling, and cytoskeleton proteins in order to play their important functional roles. TRPC proteins are incorporated into macromolecular complexes including Ca2+ signaling proteins and proteins involved in vesicle trafficking, cytoskeletal interactions, and scaffolding. Association of TRPC with calmodulin (CaM), IP3R, PMCA, Gq/11, RhoA, and a variety of scaffolding proteins has been demonstrated. The interactions between TRPC channels and adaptor proteins determines their modes of regulation as well as their cellular localizations and functions. Adaptor proteins are involved in assembling Ca2+signaling complexes, in the correct sub-cellular localization of protein partners, and in the regulation of TRPC channelosome.The S4 - S5 linker is the gear box of TRP channel gating, and many pathogenic mutations occur in this region (Hofmann et al. 2017). High resolution structures are known for TRPV1, TRPV2, TRPV6, TRPA1, and TRPP2 (Hofmann et al. 2017).
Mechanosensory transduction for senses such as proprioception, touch, balance, acceleration, hearing and pain relies on mechanotransduction channels, which convert mechanical stimuli into electrical signals in specialized sensory cells. There are two major models. One is the membrane-tension model: force applied to the membrane generates a change in membrane tension that is sufficient to gate the channel, as in bacterial MscL channels (TC# 1.A.22) and certain eukaryotic potassium channels (TC# 1.A.1). The other is the tether model: force is transmitted via a tether to gate the channel. The transient receptor potential (TRP) channel NOMPC is important for mechanosensation-related behaviours such as locomotion, touch and sound sensation across different species including Caenorhabditis elegans, Drosophila and zebrafish. NOMPC is the founding member of the TRPN subfamily, and is thought to be gated by tethering of its ankyrin repeat domain to microtubules of the cytoskeleton (Jin et al. 2017).
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Wong, F., E.L. Schaefer, B.C. Roop, J.N. LaMendola, D. Johnson-Seaton, and D. Shao. (1989). Proper function of the Drosophila trp gene product during pupal development is important for normal visual transduction in the adult. Neuron 3: 81-94.
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Zhou, Y., P. Castonguay, E.H. Sidhom, A.R. Clark, M. Dvela-Levitt, S. Kim, J. Sieber, N. Wieder, J.Y. Jung, S. Andreeva, J. Reichardt, F. Dubois, S.C. Hoffmann, J.M. Basgen, M.S. Montesinos, A. Weins, A.C. Johnson, E.S. Lander, M.R. Garrett, C.R. Hopkins, and A. Greka. (2017). A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models. Science 358: 1332-1336.
Zimmermann, K., J.K. Lennerz, A. Hein, A.S. Link, J.S. Kaczmarek, M. Delling, S. Uysal, J.D. Pfeifer, A. Riccio, and D.E. Clapham. (2011). Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system. Proc. Natl. Acad. Sci. USA 108: 18114-18119.
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Transient receptor potential (TRP) protein. Assembles in vivo as a homomultimeric channel, not as a heteromeric channel with TrpL as the subunit (Katz et al. 2013).
Transient receptor potential ion channel protein, TRP6, OF 2341 aas and 6 - 9 TMSs.
Flagellar associated calcium channel protein of 1,729 aas, FAP148 (Wheeler and Brownlee 2008).
TRPC1 store-operated Ca2+ channel (Liu et al., 2003) (activated by the metabotropic [G- protein-dependent] glutamate receptor, mGluR1) (Kim et al., 2003) (controls salivary gland fluid secretion in mice (Liu et al., 2007a). Constitutively active TRPC1/C4-dependent background Ca2+ entry fine-tunes Ca2+ cycling in beating adult cardiomyocytes. Double TRPC1/C4-gene inactivation protects against development of maladaptive cardiac remodelling without altering cardiac or extracardiac functions contributing to this pathogenesis (Camacho Londoño et al. 2015). Regulated by drebrin (DBN1; 649 aas; Q16643) (Pabon et al. 2017).
Sperm TRP-3 (SPE-41) Ca2+-permeable channel. Translocated from vesicles to the plasma membrane upon sperm activation in a process dependent on the 4TMS SPE-38 protein (8.A.36.1.1) (Singaravelu et al., 2012) during sperm-egg interactions leading to fertilization (Xu et al., 2003).
Short transient receptor channel 5 (TrpC5 or Htrp5) (transports Ca2+ and Sr2+ in the presence of Orai1 and STIM1 (TC# 1.A.52.1.1) (Ma et al., 2008). It is a cold-transducer in the peripheral nervous system (Zimmermann et al., 2011). A small-molecule inhibitor suppresses progressive kidney disease in rats (Zhou et al. 2017). ORAI and TRP, and the transmembrane Ca2+ sensors, stromal interaction molecules (STIMs), are involved in thrombosis and thrombo-inflammation in platelets and immune cells. Disregulated store-operated Ca2+ (SOCE) fluxes in platelets and immune cells are responsible, and the potential of SOCE inhibition as a therapeutic option to prevent or treat arterial thrombosis as well as thrombo-inflammatory disease states such as ischemic stroke have been considered (Mammadova-Bach et al. 2019).
Vanilloid receptor subtype 1 (VR1 or TRPV1) (noxious, heat-sensitive [opens with increasing temperatures; e.g., >42°C]; also sensitive to acidic pH and voltage and inflamation; serves as the receptor for the alkaloid irritant, capsaicin, for resiniferatoxin and for endo-cannabinoids (Murillo-Rodriguez et al. 2017). It is regulated by bradykinin and prostaglandin E2) (contains a C-terminal region, adjacent to the channel gate, that determines the coupling of stimulus sensing and channel opening (Garcia-Sanz et al., 2007; Matta and Ahern, 2007). Activated and sensitized by local anesthetics in sensory neurons (Leffler et al., 2008). A bivalent tarantula toxin activates the capsaicin receptor (TRPV1) by targeting the outer pore domain (Bohlen et al., 2010). Single-channel properties of TRPV1 are modulated by phosphorylation (Studer and McNaughton, 2010). TRPV1 mediates an itch associated response (Kim et al., 2011). The thermosensitive TRP channel pore turret is part of the temperature activation apparatus (Yang et al., 2010). Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels have been identified (Yao et al., 2011). TRPV1 opening is associated with major structural rearrangements in the outer pore, including the pore helix and selectivity filter, as well as pronounced dilation of a hydrophobic constriction at the lower gate, suggesting a dual gating mechanism (Cao et al. 2013). Allosteric coupling between upper and lower gates may account for modulation exhibited by TRPV1 and other TRP channels (Liao et al. 2013). Regulates longevity and metabolism by neuropeptides in mice (Riera et al. 2014). The pore of TRPV1 contains the structural elements sufficient for activation by noxious heat (Zhang et al. 2017).
TRPV6 epithelial Ca2+ channel (ECaC2) (forms homo- and heterotetrameric channels with TRPV5; requires the S100A10-annexin 2 complex for routing to the plasma membrane) (Hoenderop et al., 2003; van de Graaf et al., 2003). Epithelial TrpV6, but not TrpV5, is inhibited by the regulator of G-protein signaling 2 (RGS2; Q9JHX0; 211 aas) by direct binding (Schoeber et al., 2006). Cyclophilin B is an accessory activating protein (Stumpf et al., 2008). The crystal structure of rat TRPV6 at 3.25 A resolution revealed shared and unique features compared with other TRP channels (Saotome et al. 2016). Intracellular domains engage in extensive interactions to form an intracellular 'skirt' involved in allosteric modulation. In the K+ channel-like transmembrane domain, Ca2+ selectivity is determined by direct coordination of Ca2+ by a ring of aspartate side chains in the selectivity filter (Saotome et al. 2016). Replacing Gly-516 within the cytosolic S4-S5 linker (conserved in all TRP channel proteins) by ser forces the channels into an open conformation, thereby enhancing constitutive Ca2+ entry and preventing inactivation (Hofmann et al. 2016). Tetrameric ion channels have either swapped or non-swapped arrangements of the S1-S4 and pore domains. Singh et al. 2017 showed that mutations in the transmembrane domain can result in conversion from a domain-swapped to the non-swapped fold. These results raise the possibility that a single ion channel subtype can fold into either arrangement in vivo, affecting its function in normal or disease states. Cryo-EM structures of human TRPV6 in the open and closed states shows that the channel selectivity filter adopts similar conformations in both states, consistent with its explicit role in ion permeation. The iris-like channel opening is accompanied by an alpha-to-pi-helical transition in the pore-lining transmembrane helix S6 at an alanine hinge just below the selectivity filter. As a result of this transition, the S6 helices bend and rotate, exposing different residues to the ion channel pore in the open and closed states (McGoldrick et al. 2017). TRPV6 is an epithelial Ca2+-selective channel associated with transient neonatal hyperparathyroidism (TNHP), an autosomal-recessive disease caused by TRPV6 mutations that affect maternal-fetal calcium transport (Suzuki et al. 2018). TRPV6 mediates calcium uptake in epithelia, and its expression increases in numerous types of cancer while inhibitors suppress tumor growth. Singh et al. 2018 presented crystal and cryo-EM structures of human and rat TRPV6 bound to 2-aminoethoxydiphenyl borate (2-APB), a TRPV6 inhibitor and modulator of numerous TRP channels. 2-APB binds to TRPV6 in a pocket formed by the cytoplasmic half of the S1-S4 transmembrane helix bundle. 2-APB induces TRPV6 channel closure by modulating protein-lipid interactions. The 2-APB binding site may be present in other members of vanilloid subfamily TRP channels. The crystal structure has been determined (PMID# 30299652).
Intestinal endocyte Ca2+ (Sr2+; Ba2+) entry channel, CaT1. Excision of the Trpv6 gene leads to severe defects in epididymal Ca2+ absorption and male fertility as does the single D541A pore mutation (Weissgerber et al., 2012).
The noxious heat (>52°C)-sensitive vanilloid-like receptor cation selective channel, TRPV2. Ca2+-dependent desensitization of TRPV2 channels is mediated by hydrolysis of phosphatidylinositol 4,5-bisphosphate (Mercado et al., 2010). Deleting the first N-terminal 74 residues preceding the ankyrin repeat domain (ARD) shows a key role for this region in targeting the protein to the membrane. Co-translational insertion of the membrane-embedded region occurs with the TM1-TM4 and TM5-TM6 regions assembling as independent folding domains. ARD is not required for TM domain insertion into the membrane (Doñate-Macian et al. 2015). The TRPV2 structure has been solved at 4 Å resolution by cryoEM (Zubcevic et al. 2016).
TrpV-type Osm-2 (OSM2) chemo-, osmo- and touch sensation receptor channel (Xiao and Xu 2009).
Vacuolar, voltage-dependent cation-selective, Ca2+-activated channel, YVC1. (Yeast vacuolar conductance protein 1; also called TrpY1; Yor088w) (Chang et al., 2009). Activated by stretch to release vacuolar Ca2+ into the cytoplasm upon osmotic upshock. (Activated by glucose, indole and other aromatic compounds (Haynes et al., 2008; Groppi et al. 2011)). Glutathione activates by reversible glutathionylation of specific cysteyl residues in YVC1 (Chandel et al. 2016). Channel activity is activated by cytoplasmic Ca2+ and inhibited by vacuolar lumen Ca2+, and two residues, D401 and D405, are involved in Ca2+ sensing in the lumen (Amini et al. 2018).
Mg2+-selective channel/kinase-1; Mg2+-ATP-regulated divalent cation channel, LTRPC7, TRPM7, or TRP-PLIK, of 1862 aas. Bradykinin regulates TRPM7 and its downstream target annexin-1 through a phospholipase C-dependent, protein kinase C-dependent and c-Src-dependent pathway that is cAMP-independent; effects are mediated through the bradykinin type 2 receptor (Callera et al. 2009). TRPM7 is a Mg2+ sensor and transducer of signaling pathways during stressful environmental conditions. Its kinase can act on its own in chromatin remodeling processes, but TRPM6's kinase activity regulates intracellular trafficking of TRPM7 and TRPM7-dependent cell growth (Cabezas-Bratesco et al. 2015). Syndecans (proteoglycans) regulate TRPC channels to control cytosolic calcium equilibria and consequent cell behavior. In fibroblasts, ligand interactions with heparan sulfate of syndecan-4 recruit cytoplasmic protein kinase C to target serine714 of TRPC7 with subsequent control of the cytoskeleton and the myofibroblast phenotype (Gopal et al. 2015). May be associated with melanocytic tumors. Phenanthrenes, naltriben derivatives, are stimulatory agonist of the TRPM7 channel (Liu et al. 2016).
TrpCC family member, Gon2.  Required for initiation and continuation of postembryonic mitotic cell division of gonadal cells Z1 and Z4. Zygotic expression is necessary for hermaphrodite fertility. Probably a cation channel that functions together with Gem1 (TC#2.A.1.13.22) (Kemp et al. 2009).
TRPM8 of the collared flycatcher of 1103 aas. It is 83% identical to the human ortholog. Its structure has been determined to ~4.1 Å resolution by cryo EM (Yin et al. 2018). The structure reveals a three-layered architecture. The amino-terminal domain with a fold distinct among known TRP structures, together with the carboxyl-terminal region, forms a large two-layered cytosolic ring that extensively interacts with the transmembrane channel layer. The structure suggests that the menthol-binding site is located within the voltage-sensor-like domain and thus provides a structural glimpse of the design principle of the molecular transducer for cold and menthol sensation (Yin et al. 2018).
Transient receptor potential cation channel subfamily, member 3. Activated by muscarinic receptor activation. An alternative ion permeation pathway in TRPM3 allows large inward currents upon hyperpolarization, independently of the central pore. Four residues in S4 (W982, R985, D988 and G991) are crucial determinants of the properties of the alternative ion permeation pathway (Held et al. 2018).
Cold-sensitive (opens with decreasing temperatures; e.g., <22°C) and menthol-sensitive cation-selective channel, transient receptor potential melastatin 8 (TRPM8). TRPM8 is activated by low temperatures and cooling agents such as menthol. It underlies the cold-induced excitation of sensory neurons. Its gating is regulated by voltage and lysophospholipids which induce prolonged channel opening (Vanden Abeele et al., 2006; Bautista et al., 2007; Matta and Ahern, 2007). It can be converted to an anion-selective channel by introducing a lysyl residue in TMS 6 (Kuhn et al., 2007). Gating of TRPM8 channels is activated by cold and chemical agonists in planar lipid bilayers (Zakharian et al., 2010). Residues involved in intra- and intersubunit interactions have been identified, and their link with channel activity, sensitivity to icilin, menthol and cold, and their impact on channel oligomerization have been measured (Bidaux et al. 2015). Targeting the small isoform of TRPM8 may be useful to fight prostate cancer (Bidaux et al. 2016). The human isoform is 83% identical to the TRPM8 of the collared flycatcher (TC# 1.A.4.5.13), the structure of which has been characterized to 4.1 Å resolution (Yin et al. 2018). Activation of TRPM8 by cooling compounds relies on allosteric actions of agonist and the membrane lipid, phosphatidylinositol 4,5-bisphosphate (PIP2). The cryoEM structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP2, and Ca2+, as well as in complex with the menthol analog WS-12 and PIP2 revealed the binding sites for cooling agonists and PIP2 in TRPM8. PIP2 binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP2 and agonists.
4TMS-TRPM8 isoforms form functional channels in the ER and participate in regulation of the steady-state Ca2+ concentration in mitochondria and the ER. 4TMS-TRPM8 isoforms are ER Ca2+ release channels (Bidaux et al. 2018). Human PIRT (TC# 8.A.64) attenuates human TPRM8 conductance, unlike mouse PIRT, which enhances mouse TRPM8 conductance (Hilton et al. 2018). PIRT and the TRPM8 S1–S4 domain interact with a 1:1 binding stoichiometry, suggesting that a functional tetrameric TRPM8 channel has four PIRT-binding sites (Hilton et al. 2018). TRPM8 has been implicated in nociception and pain and is regarded as an attractive target for the pharmacological treatment of neuropathic pain syndromes. A series of analogues of N,N'-dibenzyl tryptamine 1, a potent TRPM8 antagonist, were made and studied. Molecular modeling studies identified the putative binding mode of these antagonists, suggesting that they could influence an interaction network between the S1-4 transmembrane segments and the TRP domains of the channel subunits (Bertamino et al. 2018). Cold sensitivity is due to nonconserved residues located within the pore loop (residues 526 - 556) (Pertusa et al. 2018).
The nociceptive neuron TRPA1 (Trp-ankyrin 1) senses peripheral damage by transmitting pain signals (activated by cold temperatures, pungent compounds and environmental irritants). Noxious compounds also activate through covalent modification of cysteyl residues (Macpherson et al., 2007). TRPA1 is an excitatory, nonselective cation channel implicated in somatosensory function, pain, and neurogenic inflammation. Through covalent modification of cysteine and lysine residues, TRPA1 can be activated by electrophilic compounds, including active ingredients of pungent natural products (e.g., allyl isothiocyanate), environmental irritants (e.g., acrolein), and endogenous ligands (4-hydroxynonenal) (Chen et al., 2008). General anesthetics activate TRPA1 nociceptive ion channels to enhance pain and inflammation (Matta et al., 2008; Leffler et al., 2011). TMS5 is a critical molecular determinant of menthol sensitivity (Xiao et al., 2008) and a variety of inhibitors which are analgesics. Another class of inhibitors are in the thiadiazole structural class of compounds, and they bind to the TRPA1 ankyrin repeat 6 (Tseng et al. 2018). Inhibitors are potential analgesics. The majority of TRPA1 inhibitors interact with the S5 transmembrane helices, forming part of the pore region of the channel. TRPA1 is a component of the nociceptive response to CO2 (Wang et al., 2010). TRPA1 is a polyunsaturated fatty acid sensor in mammals but not in flies and fish (Motter and Ahern, 2012). It is regulated by its N-terminal ankyrin repeat domain (Zayats et al., 2012). Mutations in TrpA1 cause alterred pain perception (Kremeyer et al. 2010). The hop compound, eudesmol, an oxygenated sesquiterpene, activates the channel (Ohara et al. 2015). These channels regulate heat and cold perception, mechanosensitivity, hearing, inflammation, pain, circadian rhythms, chemoreception, and other processes (Laursen et al. 2014). TRPA1 is a polymodal ion channel sensitive to temperature and chemical stimuli, but its resposes are species specific (Laursen et al. 2015). A probable binding site for general anesthetics has been identified (Ton et al. 2017), and specific residues involved in binding of the anesthetic, propofol, are known (Woll et al. 2017). TrpV1 and TrpA1 are inflammatory mediators causing cutaneous chronic itch in several diseases (Xie and Li 2018). TRPA1 is specifically activated by natural products including allyl isothiocyanate (mustard oil), cinnamaldehyde (cinnamon), allicin (garlic) and trans-anethole in Fennel Oil (FO) (Memon et al. 2019).
Thermosensitive TPR channel TRPA1 (TrpA-1) of 1211 aas. Detects a temperature drop promoting increased longevity. This requires TPRA1-mediated Ca2+ influx and activation of protein kinase C. Human TRPA1 (TC# 1.A.4.6.3) can functionally substitute for worm TRPA-1 in promoting longevity (Xiao et al. 2013). Also mediates touch sensation.
The sensory ion channel in tactile bristles of insects, NompC. The atomic structure of Drosophila NOMPC has been determined by single-particle electron cryo-microscopy. Structural analyses suggested that the ankyrin repeat domain (29 repeats) of NOMPC resembles a helical spring, suggesting its role of linking mechanical displacement of the cytoskeleton to the opening of the channel (Jin et al. 2017). Compression of the ankyrin chains imparts a rotational torque on the TRP domain, which may result in channel opening (Argudo et al. 2019).
The pore forming subunit, Trp-4, a mechanosensitive cation/Ca2+ channel. Present in ciliated mechanosensitive neurons; Activation and latency occur in the microsecond range. trp-4 mutations alter ion selectivity (Kang et al., 2010; Xiao and Xu 2009).
Flavin carrier protein 2, Flc2p. May be responsible for the transport of FAD (and heme) into the endoplasmic reticulum lumen, where FAD may be required for oxidative protein folding involved in disulfide bridge formation (Protchenko et al. 2006).

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