document_idx
int64 0
21
| text
stringclasses 52
values | page_idx
int64 31
41
| document_name
stringclasses 1
value | file_path
stringclasses 1
value | file_url
stringclasses 1
value | loader_name
stringclasses 1
value |
|---|---|---|---|---|---|---|
15 | artificial siRNAs as a therapeutic tool for silencing disease-related genes. | 35 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
16 | Cell structure
7
1
RETPaHC
A B
N
GG
V
GG M
C Phagocytic pathway Secretory pathway Membrane recycling Receptor-mediated endocytosis
Clathrin-coated pit
Early endosome
Late endosome
Lysosomal
fusion
Secondary lysosome
Residual body
Vesicle shuttling
between cisternae trans-Golgi network
Golgi cisternae
cis-Golgi network
Rough endoplasmic
reticulum
D E
G
R
Fig . 1 .5 The Golgi apparatus and functionally related organelles . A, Golgi apparatus (G) adjacent to the nucleus (N) (V, vesicle) . B, A large residual body
(tertiary lysosome) in a cardiac muscle cell (M, mitochondrion) . C, The functional relationships between the Golgi apparatus and associated cellular
structures . D, A three-dimensional reconstruction of the Golgi apparatus in a pancreatic β cell showing stacks of Golgi cisternae from the cis-face (pink) | 36 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
16 | and cis-medial cisternae (red, green) to the trans-Golgi network (blue, yellow, orange–red); immature proinsulin granules (condensing vesicles) are
shown in pale blue and mature (crystalline) insulin granules in dark blue . The flat colour areas represent cut faces of cisternae and vesicles . E, Rough
endoplasmic reticulum (R), associated with the Golgi apparatus (G) . (D, Courtesy of Dr Brad Marsh, Institute for Molecular Bioscience, University of
Queensland, Brisbane . A,B,E From human tissue, courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK .) | 36 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
17 | BaSIC STRuCTuRE aNd fuNCTION Of CEllS
8
1
NOITCES
salts. Traffic between the endoplasmic reticulum and the Golgi appara- Endocytic (internalization) pathway
tus is bidirectional and takes place via carrier vesicles derived from the
The endocytic pathway begins at the plasma membrane and ends in
donor site that bud, tether and fuse with the target site.
lysosomes involved in the degradation of the endocytic cargo through
Golgins are long coiled-coil proteins attached to the cytoplasmic
the enzymatic activity of lysosomal hydrolases. Endocytic cargo is
surface of cisternal membranes, forming a fibrillar matrix surrounding
internalized from the plasma membrane to early endosomes and
the Golgi apparatus to stabilize it; they have a role in vesicle trafficking
then to late endosomes. Late endosomes transport their cargo to lyso-
(for further reading on golgins, see Munro 2011). The Golgi apparatus
somes, where the cargo material is degraded following fusion and
has several functions: it links anterograde and retrograde protein and | 37 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
17 | mixing of contents of endosomes and lysosomes. Early endosomes
lipid flow in the secretory pathway; it is the site where protein and lipid
derive from endocytic vesicles (clathrin-coated vesicles and caveolae).
glycosylation occurs; and it provides membrane platforms to which
Once internalized, endocytic vesicles shed their coat of adaptin and
signalling and sorting proteins bind.
clathrin, and fuse to form an early endosome, where the receptor
Ultrastructurally, the Golgi apparatus (Fig. 1.5A) displays a contin-
molecules release their bound ligands. Membrane and receptors from
uous ribbon-like structure consisting of a stack of several flattened
the early endosomes can be recycled to the cell surface as exocytic
membranous cisternae, together with clusters of vesicles surrounding
vesicles.
its surfaces. Cisternae differ in enzymatic content and activity. Small
Clathrin-dependent endocytosis occurs at specialized patches of
transport vesicles from the rough endoplasmic reticulum are received
plasma membrane called coated pits; this mechanism is also used to | 37 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
17 | at one face of the Golgi stack, the convex cis-face (entry or forming
internalize ligands bound to surface receptor molecules and is also
surface). Here, they deliver their contents to the first cisterna in the
termed receptor-mediated endocytosis. Caveolae (little caves) are struc-
series by membrane fusion. From the edges of this cisterna, the protein
turally distinct pinocytotic vesicles most widely used by endothelial and
is transported to the next cisterna by vesicular budding and then
smooth muscle cells, when they are involved in transcytosis, signal
fusion, and this process is repeated across medial cisternae until the
transduction and possibly other functions. In addition to late endo-
final cisterna at the concave trans-face (exit or condensing surface) is
somes, lysosomes can also fuse with phagosomes, autophagosomes
reached. Here, larger vesicles are formed for delivery to other parts of
and plasma membrane patches for membrane repair. Lysosomal hydro-
the cell.
lases process or degrade exogenous materials (phagocytosis or hetero- | 37 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
17 | The cis-Golgi and trans-Golgi membranous networks form an inte-
phagy) as well as endogenous material (autophagy). Phagocytosis
gral part of the Golgi apparatus. The cis-Golgi network is a region of
consists of the cellular uptake of invading pathogens, apoptotic cells
complex membranous channels interposed between the rough endo-
and other foreign material by specialized cells. Lysosomes are numerous
plasmic reticulum and the Golgi cis-face, which receives and transmits
in actively phagocytic cells, e.g. macrophages and neutrophil granulo-
vesicles in both directions. Its function is to select appropriate proteins
cytes, in which lysosomes are responsible for destroying phagocytosed
synthesized on the rough endoplasmic reticulum for delivery by vesicles
particles, e.g. bacteria. In these cells, the phagosome, a vesicle poten-
to the Golgi stack, while inappropriate proteins are shuttled back to the
tially containing a pathogenic microorganism, may fuse with several
rough endoplasmic reticulum.
lysosomes. | 37 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
17 | The trans-Golgi network, at the other side of the Golgi stack, is also
Autophagy involves the degradation and recycling within an
a region of interconnected membrane channels engaged in protein
autophagosome of cytoplasmic components that are no longer needed,
sorting. Here, modified proteins processed in the Golgi cisternae are
including organelles. The assembly of the autophagosome involves
packaged selectively into vesicles and dispatched to different parts of
several proteins, including autophagy-related (Atg) proteins, as well as
the cell. The packaging depends on the detection, by the trans-Golgi
Hsc70 chaperone, that translocate the substrate into the lysosome (Boya
network, of particular amino-acid signal sequences, leading to their
et al 2013). Autophagosomes sequester cytoplasmic components and
enclosure in membranes of appropriate composition that will further
then fuse with lysosomes without the participation of a late endosome.
modify their contents, e.g. by extracting water to concentrate them
The 26S proteasome (see below) is also involved in cellular degradation | 37 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
17 | (vesicles entering the exocytosis pathway) or by pumping in protons to
but autophagy refers specifically to a lysosomal degradation–recycling
acidify their contents (lysosomes destined for the intracellular sorting
pathway. Autophagosomes are seen in response to starvation and cell
pathway).
growth.
Within the Golgi stack proper, proteins undergo a series of sequen-
Late endosomes receive lysosomal enzymes from primary lysosomes
tial chemical modifications by Golgi resident enzymes synthesized
derived from the Golgi apparatus after late endosome–lysosome mem-
in the rough endoplasmic reticulum. These include: glycosylation
brane tethering and fusion followed by diffusion of lysosomal contents
(changes in glycosyl groups, e.g. removal of mannose, addition of
into the endosomal lumen. The pH inside the fused hybrid organelle,
N-acetylglucosamine and sialic acid); sulphation (addition of sulphate
now a secondary lysosome, is low (about 5.0) and this activates lyso-
groups to glycosaminoglycans); and phosphorylation (addition of | 37 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
17 | somal acid hydrolases to degrade the endosomal contents. The products
phosphate groups). Some modifications serve as signals to direct pro-
of hydrolysis either are passed through the membrane into the cytosol,
teins and lipids to their final destination within cells, including lyso-
or may be retained in the secondary lysosome. Secondary lysosomes
somes and plasma membrane. Lipids formed in the endoplasmic
may grow considerably in size by vesicle fusion to form multivesicular
reticulum are also routed for incorporation into vesicles.
bodies, and the enzyme concentration may increase greatly to form
large lysosomes (Fig. 1.5B).
Exocytic (secretory) pathway
Secreted proteins, lipids, glycoproteins, small molecules such as amines
Lysosomes
and other cellular products destined for export from the cell are trans-
ported to the plasma membrane in small vesicles released from the Lysosomes are membrane-bound organelles 80–800 nm in diameter,
trans-face of the Golgi apparatus. This pathway either is constitutive, in often with complex inclusions of material undergoing hydrolysis (sec- | 37 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
17 | which transport and secretion occur more or less continuously, as with ondary lysosomes). Two classes of proteins participate in lysosomal
immunoglobulins produced by plasma cells, or it is regulated by exter- function: soluble acid hydrolases and integral lysosomal membrane
nal signals, as in the control of salivary secretion by autonomic neural proteins. Each of the 50 known acid hydrolases (including proteases,
stimulation. In regulated secretion, the secretory product is stored tem- lipases, carbohydrases, esterases and nucleases) degrades a specific sub-
porarily in membrane-bound secretory granules or vesicles. Exocytosis strate. There are about 25 lysosomal membrane proteins participating
is achieved by fusion of the secretory vesicular membrane with the in the acidification of the lysosomal lumen, protein import from the
plasma membrane and release of the vesicle contents into the extracel- cytosol, membrane fusion and transport of degradation products to the
lular domain. In polarized cells, e.g. most epithelia, exocytosis occurs cytoplasm. Material that has been hydrolysed within secondary lyso- | 37 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
17 | at the apical plasma membrane. Glandular epithelial cells secrete into somes may be completely degraded to soluble products, e.g. amino
a duct lumen, as in the pancreas, or on to a free surface, such as the acids, which are recycled through metabolic pathways. However, degra-
lining of the stomach. In hepatocytes, bile is secreted across a very small dation is usually incomplete and some debris remains. A debris-laden
area of plasma membrane forming the wall of the bile canaliculus. This vesicle is called a residual body or tertiary lysosome (see Fig. 1.5B), and
region is defined as the apical plasma membrane and is the site of may be passed to the cell surface, where it is ejected by exocytosis;
exocrine secretion, whereas secretion of hepatocyte plasma proteins alternatively, it may persist inside the cell as an inert residual body.
into the blood stream is targeted to the basolateral surfaces facing the Considerable numbers of residual bodies can accumulate in long-lived
sinusoids. Packaging of different secretory products into appropriate cells, often fusing to form larger dense vacuoles with complex lamellar | 37 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
17 | vesicles takes place in the trans-Golgi network. Delivery of secretory inclusions. As their contents are often darkly pigmented, this may
vesicles to their correct plasma membrane domains is achieved by change the colour of the tissue; e.g. in neurones, the end-product of
sorting sequences in the cytoplasmic tails of vesicular membrane lysosomal digestion, lipofuscin (neuromelanin or senility pigment),
proteins. gives ageing brains a brownish-yellow colouration. Lysosomal enzymes | 37 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
18 | Basic structure and function of cells
8.e1
1
RETPaHC
Carrier vesicles in transit from the endoplasmic reticulum to the
Golgi apparatus (anterograde transport) are coated by coat protein
complex II (COPII), whereas COPI-containing vesicles function in the
retrograde transport route from the Golgi apparatus (reviewed in Spang
(2013)).
The membranes contain specific signal proteins that may allocate
them to microtubule-based transport pathways and allow them to dock
with appropriate targets elsewhere in the cell, e.g. the plasma mem-
brane in the case of secretory vesicles. Vesicle formation and budding
at the trans-Golgi network involves the addition of clathrin on their
external surface, to form coated pits.
Specialized cells of the immune system, called antigen-presenting
cells, degrade protein molecules, called antigens, transported by the
endocytic pathway for lysosomal breakdown, and expose their frag-
ments to the cell exterior to elicit an immune response mediated ini-
tially by helper T cells. | 38 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
19 | Cell structure
9
1
RETPaHC
may also be secreted – often as part of a process to alter the extracellular A
matrix, as in osteoclast-mediated erosion during bone resorption. For
further reading on lysosome biogenesis, see Saftig and Klumperman
(2009).
lysosomal dysfunction
Lysosomal storage diseases (LSDs) are a consequence of lysosomal
dysfunction. Approximately 60 different types of LSD have been identi-
fied on the basis of the type of material accumulated in cells (such as
mucopolysaccharides, sphingolipids, glycoproteins, glycogen and lipo-
fuscins). LSDs are characterized by severe neurodegeneration, mental
decline, and cognitive and behavioural abnormalities. Autophagy
impairment caused by defective lysosome–autophagosome coupling
triggers a pathogenic cascade by the accumulation of substrates that
contribute to neurodegenerative disorders including Parkinson’s dis-
ease, Alzheimer’s disease, Huntington’s disease and several tau-opathies.
Many lysosomal storage diseases are known, e.g. Tay–Sachs disease | 39 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
19 | (GM2 gangliosidosis), in which a faulty β-hexosaminidase A leads to
the accumulation of the glycosphingolipid GM2 ganglioside in neu-
rones, causing death during childhood. In Danon disease, a vacuolar
skeletal myopathy and cardiomyopathy with neurodegeneration in
hemizygous males, lysosomes fail to fuse with autophagosomes because
of a mutation of the lysosomal membrane protein LAMP-2 (lysosomal B
associated membrane protein-2).
26S proteasome
Outer membrane
A protein can be degraded by different mechanisms, depending on
the cell type and different pathological conditions. Furthermore, the
same substrate can engage different proteolytic pathways (Park and Inner membrane
Cuervo 2013). Three major protein degradation mechanisms operate
in eukaryotic cells to dispose of non-functional cellular proteins: Cristae (folds)
the autophagosome–lysosomal pathway (see above); the apoptotic
procaspase–caspase pathway (see below); and the ubiquitinated Elementary
particles
protein–26S proteasome pathway. The 26S proteasome is a multicata- | 39 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
19 | lytic protease found in the cytosol and the nucleus that degrades intra-
cellular proteins conjugated to a polyubiquitin chain by an enzymatic
cascade. The 26S proteasome consists of several subunits arranged into
two 19S polar caps, where protein recognition and adenosine 5′-
triphosphate (ATP)-dependent target processing occur, flanking a 20S
central barrel-shaped structure with an inner proteolytic chamber
(Tomko and Hochstrasser 2013). The 26S proteasome participates in
the removal of misfolded or abnormally assembled proteins, the deg-
radation of cyclins involved in the control of the cell cycle, the process-
ing and degradation of transcription regulators, cellular-mediated Fig . 1 .6 A, Mitochondria in human cardiac muscle . The folded cristae
immune responses, and cell cycle arrest and apoptosis. (arrows) project into the matrix from the inner mitochondrial membrane .
B, The location of the elementary particles that couple oxidation and
Peroxisomes
phosphorylation reactions . (A, Courtesy of Dr Bart Wagner, | 39 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
19 | Peroxisomes are small (0.2–1 µm in diameter) membrane-bound Histopathology Department, Sheffield Teaching Hospitals, UK .)
organelles present in most mammalian cells. They contain more than
50 enzymes responsible for multiple catabolic and synthetic biochemi-
cal pathways, in particular the β-oxidation of very-long-chain fatty Mitochondria
acids (>C22) and the metabolism of hydrogen peroxide (hence the In the electron microscope, mitochondria usually appear as round or
name peroxisome). Peroxisomes derive from the endoplasmic reticu- elliptical bodies 0.5–2.0 µm long (Fig. 1.6), consisting of an outer
lum through the transfer of proteins from the endoplasmic reticulum mitochondrial membrane; an inner mitochrondrial membrane, sepa-
to peroxisomes by vesicles that bud from specialized sites of the endo- rated from the outer membrane by an intermembrane space; cristae,
plasmic reticulum and by a lipid non-vesicular pathway. All matrix infoldings of the inner membrane that harbour ATP synthase to gener- | 39 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
19 | proteins and some peroxisomal membrane proteins are synthesized by ate ATP; and the mitochondrial matrix, a space enclosed by the inner
cytosolic ribosomes and contain a peroxisome targeting signal that membrane and numerous cristae. The permeability of the two mito-
enables them to be imported by proteins called peroxins (Braverman chondrial membranes differs considerably: the outer membrane is
et al 2013, Theodoulou et al 2013). Mature peroxisomes divide by freely permeable to many substances because of the presence of large
small daughter peroxisomes pinching off from a large parental non-specific channels formed by proteins (porins), whereas the inner
peroxisome. membrane is permeable to only a narrow range of molecules. The pres-
Peroxisomes often contain crystalline inclusions composed mainly ence of cardiolipin, a phospholipid, in the inner membrane may con-
of high concentrations of the enzyme urate oxidase. Oxidases use tribute to this relative impermeability.
molecular oxygen to oxidize specific organic substrates (such as L-amino Mitochondria are the principal source of chemical energy in most | 39 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
19 | acids, D-amino acids, urate, xanthine and very-long-chain fatty acids) cells. Mitochondria are the site of the citric acid (Krebs’) cycle and the
and produce hydrogen peroxide that is detoxified (degraded) by per- electron transport (cytochrome) pathway by which complex organic
oxisomal catalase. Peroxisomes are particularly numerous in hepato- molecules are finally oxidized to carbon dioxide and water. This process
cytes. Peroxisomes are important in the oxidative detoxification of provides the energy to drive the production of ATP from adenosine
various substances taken into or produced within cells, including diphosphate (ADP) and inorganic phosphate (oxidative phosphoryla-
ethanol. Peroxin mutation is a characteristic feature of Zellweger syn- tion). The various enzymes of the citric acid cycle are located in the
drome (craniofacial dysmorphism and malformations of brain, liver, mitochondrial matrix, whereas those of the cytochrome system and
eye and kidney; cerebrohepatorenal syndrome). Neonatal leukodystro- oxidative phosphorylation are localized chiefly in the inner mitochon- | 39 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
19 | phy is an X-linked peroxisomal disease affecting mostly males, caused drial membrane.
by deficiency in β-oxidation of very-long-chain fatty acids. The build-up The intermembrane space houses cytochrome c, a molecule involved
of very-long-chain fatty acids in the nervous system and suprarenal in activation of apoptosis.
glands determines progressive deterioration of brain function and The number of mitochondria in a particular cell reflects its general
suprarenal insufficiency (Addison’s disease). For further reading, see energy requirements; e.g. in hepatocytes there may be as many as 2000,
Braverman et al (2013). whereas in resting lymphocytes there are usually very few. Mature | 39 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
20 | Basic structure and function of cells
9.e1
1
RETPaHC
The transcription factor EB (TFEB) is responsible for regulating lyso-
somal biogenesis and function, lysosome-to-nucleus signalling and
lipid catabolism (for further reading, see Settembre et al (2013)). If any
of the actions of lysosomal hydrolases, of the lysosome acidification
mechanism or of lysosomal membrane proteins fails, the degradation
and recycling of extracellular substrates delivered to lysosomes by the
late endosome and the degradation and recycling of intracellular sub-
strates by autophagy lead to progressive lysosomal dysfunction in
several tissues and organs.
Experimentally, TFEB activation can reduce the accumulation of
the pathogenic protein in a cellular model of Huntington’s disease (a
neurodegenerative genetic disorder that affects muscle coordination)
and improves the Parkinson’s disease phenotype in a murine model.
Cristae are abundant in mitochondria seen in cardiac muscle
cells and in steroid-producing cells (in the suprarenal cortex, corpus
luteum and Leydig cells). The protein steroidogenic acute regulatory
protein (StAR) regulates the synthesis of steroids by transporting | 40 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
20 | cholesterol across the outer mitochondrial membrane. A mutation
in the gene encoding StAR causes defective suprarenal and gonadal
steroidogenesis. | 40 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
21 | BaSIC STRuCTuRE aNd fuNCTION Of CEllS
10
1
NOITCES
erythrocytes lack mitochondria altogether. Cells with few mitochondria ent and its electronic charge, and the potential difference across the
generally rely largely on glycolysis for their energy supplies. These membrane. These factors combine to produce an electrochemical gradi-
include some very active cells, e.g. fast twitch skeletal muscle fibres, ent, which governs ion flux. Channel proteins are utilized most effec-
which are able to work rapidly but for only a limited duration. Mito- tively by the excitable plasma membranes of nerve cells, where the
chondria appear in the light microscope as long, thin structures in the resting membrane potential can change transiently from about −80 mV
cytoplasm of most cells, particularly those with a high metabolic rate, (negative inside the cell) to +40 mV (positive inside the cell) when
e.g. secretory cells in exocrine glands. In living cells, mitochondria stimulated by a neurotransmitter (as a result of the opening and sub- | 41 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
21 | constantly change shape and intracellular position; they multiply by sequent closure of channels selectively permeable to sodium and
growth and fission, and may undergo fusion. potassium).
The mitochondrial matrix is an aqueous environment. It contains a Carrier proteins bind their specific solutes, such as amino acids, and
variety of enzymes, and strands of mitochondrial DNA with the capacity transport them across the membrane through a series of conforma-
for transcription and translation of a unique set of mitochondrial genes tional changes. This latter process is slower than ion transport through
(mitochondrial mRNAs and transfer RNAs, mitochondrial ribosomes membrane channels. Transport by carrier proteins can occur either pas-
with rRNAs). The DNA forms a closed loop, about 5 µm across; several sively by simple diffusion, or actively against the electrochemical gradi-
identical copies are present in each mitochondrion. The ratio between ent of the solute. Active transport must therefore be coupled to a source
its bases differs from that of nuclear DNA, and the RNA sequences also of energy, such as ATP generation, or energy released by the coordinate | 41 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
21 | differ in the precise genetic code used in protein synthesis. At least 13 movement of an ion down its electrochemical gradient. Linked trans-
respiratory chain enzymes of the matrix and inner membrane are port can be in the same direction as the solute, in which case the carrier
encoded by the small number of genes along the mitochondrial DNA. protein is described as a symporter, or in the opposite direction, when
The great majority of mitochondrial proteins are encoded by nuclear the carrier acts as an antiporter.
genes and made in the cytosol, then inserted through special channels
in the mitochondrial membranes to reach their destinations. Their Translocation of proteins across
membrane lipids are synthesized in the endoplasmic reticulum. intracellular membranes
It has been shown that mitochondria are of maternal origin because Proteins are generally synthesized on ribosomes in the cytosol or on
the mitochondria of spermatozoa are not generally incorporated the rough endoplasmic reticulum. A few are made on mitochondrial
into the ovum at fertilization. Thus mitochondria (and mitochondrial ribosomes. Once synthesized, many proteins remain in the cytosol, | 41 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
21 | genetic variations and mutations) are passed only through the where they carry out their functions. Others, such as integral membrane
female line. proteins or proteins for secretion, are translocated across intracellular
Mitochondria are distributed within a cell according to regional membranes for post-translational modification and targeting to their
energy requirements, e.g. near the bases of cilia in ciliated epithelia, in destinations. This is achieved by the signal sequence, an addressing
the basal domain of the cells of proximal convoluted tubules in the system contained within the protein sequence of amino acids, which is
renal cortex (where considerable active transport occurs) and around recognized by receptors or translocators in the appropriate membrane.
the proximal segment, called middle piece, of the flagellum in sperma- Proteins are thus sorted by their signal sequence (or set of sequences
tozoa. They may be involved with tissue-specific metabolic reactions, that become spatially grouped as a signal patch when the protein folds
e.g. various urea-forming enzymes are found in liver cell mitochondria. into its tertiary configuration), so that they are recognized by and enter | 41 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
21 | Moreover, a number of genetic diseases of mitochondria affect particu- the correct intracellular membrane compartment.
lar tissues exclusively, e.g. mitochondrial myopathies (skeletal muscle)
and mitochondrial neuropathies (nervous tissue). For further informa-
Cell signalling
tion on mitochondrial genetics and disorders, see Chinnery and Hudson
(2013).
Cellular systems in the body communicate with each other to coordi-
Cytosolic inclusions nate and integrate their functions. This occurs through a variety of
The aqueous cytosol surrounds the membranous organelles described processes known collectively as cell signalling, in which a signalling
above. It also contains various non-membranous inclusions, including molecule produced by one cell is detected by another, almost always by
free ribosomes, components of the cytoskeleton, and other inclusions, means of a specific receptor protein molecule. The recipient cell trans-
such as storage granules (e.g. glycogen), pigments (such as lipofuscin duces the signal, which it most often detects at the plasma membrane,
granules, remnants of the lipid oxidative mechanism seen in the supra- into intracellular chemical messages that change cell behaviour. | 41 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
21 | renal cortex) and lipid droplets. The signal may act over a long distance, e.g. endocrine signalling
through the release of hormones into the blood stream, or neuronal
lipid droplets synaptic signalling via electrical impulse transmission along axons
Lipid droplets are spherical bodies of various sizes found within many and subsequent release of chemical transmitters of the signal at syn-
cells, but are especially prominent in the adipocytes (fat cells) of apses or neuromuscular junctions. A specialized variation of endocrine
adipose connective tissue. They do not belong to the Golgi-related vacu- signalling (neurocrine or neuroendocrine signalling) occurs when neu-
olar system of the cell. They are not membrane-bound, but are droplets rones or paraneurones (e.g. chromaffin cells of the suprarenal medulla)
of lipid suspended in the cytosol and surrounded by perilipin proteins, secrete a hormone into interstitial fluid and the blood stream.
which regulate lipid storage and lipolysis. See Smith and Ordovás Alternatively, signalling may occur at short range through a paracrine | 41 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
21 | (2012) for further reading on obesity and perilipins. In cells specialized mechanism, in which cells of one type release molecules into the inter-
for lipid storage, the vacuoles reach 80 µm or more in diameter. They stitial fluid of the local environment, to be detected by nearby cells of
function as stores of chemical energy, thermal insulators and mechani- a different type that express the specific receptor protein. Neurocrine
cal shock absorbers in adipocytes. In many cells, they may represent cell signalling uses chemical messengers found also in the central
end-products of other metabolic pathways, e.g. in steroid-synthesizing nervous system, which may act in a paracrine manner via interstitial
cells, where they are a prominent feature of the cytoplasm. They may fluid or reach more distant target tissues via the blood stream. Cells
also be secreted, as in the alveolar epithelium of the lactating breast. may generate and respond to the same signal. This is autocrine signal-
ling, a phenomenon that reinforces the coordinated activities of a group
Transport across cell membranes of like cells, which respond together to a high concentration of a local | 41 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
21 | Lipid bilayers are increasingly impermeable to molecules as they signalling molecule. The most extreme form of short-distance signalling
increase in size or hydrophobicity. Transport mechanisms are therefore is contact-dependent (juxtacrine) signalling, where one cell responds to
required to carry essential polar molecules, including ions, nutrients, transmembrane proteins of an adjacent cell that bind to surface recep-
nucleotides and metabolites of various kinds, across the plasma mem- tors in the responding cell membrane. Contact-dependent signalling
brane and into or out of membrane-bound intracellular compartments. also includes cellular responses to integrins on the cell surface binding
Transport is facilitated by a variety of membrane transport proteins, to elements of the extracellular matrix. Juxtacrine signalling is impor-
each with specificity for a particular class of molecule, e.g. sugars. Trans- tant during development and in immune responses. These different
port proteins fall mainly into two major classes: channel proteins and types of intercellular signalling mechanism are illustrated in Figure 1.7.
carrier proteins. For further reading on cell signalling pathways, see Kierszenbaum and
Channel proteins form aqueous pores in the membrane, which open Tres (2012). | 41 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |
21 | and close under the regulation of intracellular signals, e.g. G-proteins,
Signalling molecules and their receptors
to allow the flux of solutes (usually inorganic ions) of specific size and
charge. Transport through ion channels is always passive, and ion flow The majority of signalling molecules (ligands) are hydrophilic and so
through an open channel depends only on the ion concentration gradi- cannot cross the plasma membrane of a recipient cell to effect changes | 41 | Gray's Anatomy | temp.pdf | null | PDFPlumberTextLoader |