14 The Cell(continued amino acids)into the cytoplasm and (b)en- membrane are proteins that make up 25%(my- ure charge tion during H* uptake elin membrane)to 75% (inner mitochondr (CI-channels). These enzymes and transport membrane)of the membrane mass, depend roteins are delivered in primary lysosomes ing on the membrane type. Many of them spa om the Golgi apparatus. Mannose-6- the entire lipid bilayer once(G1)or sever a Posphate(M6P)serves as the"label"for this times (G2)(transmembrane proteins). rocess; it binds to M6P receptors in the Golgi thereby serving as ion channels, carrier pi E mediated endocytosis (p. 28 ). cluster in the anchored by their lipophilic amino acid res w membrane with the help of a clathrin frame mes,the enzymes and transport proteins are the membrane, whereas others, like the anio parated from the receptor, and M6P is de- exchanger of red cells, are anchored to the cy- 2 phosphorylated. The M6P receptor returns to toskeleton. The cell surface is largely covered the Golgi apparatus(recycling, -F). The M6P by the glycocalyx, which consists of sugar receptor no longer recognizes the dephospho- moieties of glycoproteins and glycolipids in rylated proteins, which prevents them from the cell membrane (G1,. 4)and of the extra- returning to the Golgi apparatu cellular matrix. The glycocalyx mediates cell- Peroxisomes are microbodies containing cell interactions (surface recognition, cell nzymes (imported via a signal sequence)that docking, etc. ) For example, components of the ermit the oxidation of certain organic glycocalyx of neutrophils dock onto en- molecules(R-H2, such as amino acids and dothelial membrane proteins, called selectins fatty acids: R-H2+02R+H202. The peroxi- (p. 94). omes also contain catalase, which transforms The cytoskeleton allows the cell to maintain 2H2O2 into O2+ H2O and oxidizes toxins, such and change its shape(during cell division, etc. ) as alcohol and other substances Whereas the membrane of organelles is re- and conduct intracellular transport activities sponsible for intracellular compartmentaliza- (vesicle, mitosis). It contains actin filaments a on, the main job of the cell membrane(G) well as microtubules and intermediate fila- to eparate the cell interior from the extra- ments (e. g, vimentin and desmin filaments, cellular space(p 2). The cell membrane is a neurofilaments, keratin filaments )that extend ospholipid bilayer(G1)that may be either from the centrosome. tooth or deeply infolded, like the brush on the cell type, the cell membrane contains variable amounts of phospholipids, cholestero and glycolipids(e.g, cerebrosides ). The phos pholipids mainly consist of phosphatidylch ethanolamine, and sphingomyelin. The hy ach other, whereas the hydrophilic co he extracellular fluid or cytosol (G4). Th Did composition of the two layers of the nembrane differs greatly. Glycol esent only in the external layer, as described elow. Cholesterol (present in both layers)re duces both the fluidity of the membrane and its permeability to polar substances. within ly fluid phospholipid
141 Fundamentals and Cell Physiology amino acids) into the cytoplasm and (b) ensure charge compensation during H+ uptake (Cl– channels). These enzymes and transport proteins are delivered in primary lysosomes from the Golgi apparatus. Mannose-6- phosphate (M6 P) serves as the “label” for this process; it binds to M6 P receptors in the Golgi membrane which, as in the case of receptormediated endocytosis ( p. 28 ), cluster in the membrane with the help of a clathrin framework. In the acidic environment of the lysosomes, the enzymes and transport proteins are separated from the receptor, and M6 P is dephosphorylated. The M6 P receptor returns to the Golgi apparatus (recycling, F). The M6 P receptor no longer recognizes the dephosphorylated proteins, which prevents them from returning to the Golgi apparatus. Peroxisomes are microbodies containing enzymes (imported via a signal sequence) that permit the oxidation of certain organic molecules (R-H2), such as amino acids and fatty acids: R-H2 + O2 R+H2O2. The peroxisomes also contain catalase, which transforms 2 H2O2 into O2 + H2O and oxidizes toxins, such as alcohol and other substances. Whereas the membrane of organelles is responsible for intracellular compartmentalization, the main job of the cell membrane ( G) is to separate the cell interior from the extracellular space ( p. 2). The cell membrane is a phospholipid bilayer ( G1) that may be either smooth or deeply infolded, like the brush border or the basal labyrinth ( B). Depending on the cell type, the cell membrane contains variable amounts of phospholipids, cholesterol, and glycolipids (e.g., cerebrosides). The phospholipids mainly consist of phosphatidylcholine ( G3), phosphatidylserine, phosphatidylethanolamine, and sphingomyelin. The hydrophobic components of the membrane face each other, whereas the hydrophilic components face the watery surroundings, that is, the extracellular fluid or cytosol ( G4). The lipid composition of the two layers of the membrane differs greatly. Glycolipids are present only in the external layer, as described below. Cholesterol (present in both layers) reduces both the fluidity of the membrane and its permeability to polar substances. Within the two-dimensionally fluid phospholipid membrane are proteins that make up 25% (myelin membrane) to 75% (inner mitochondrial membrane) of the membrane mass, depending on the membrane type. Many of them span the entire lipid bilayer once ( G1) or several times ( G2) (transmembrane proteins), thereby serving as ion channels, carrier proteins, hormone receptors, etc. The proteins are anchored by their lipophilic amino acid residues, or attached to already anchored proteins. Some proteins can move about freely within the membrane, whereas others, like the anion exchanger of red cells, are anchored to the cytoskeleton. The cell surface is largely covered by the glycocalyx, which consists of sugar moieties of glycoproteins and glycolipids in the cell membrane ( G1,4) and of the extracellular matrix. The glycocalyx mediates cell– cell interactions (surface recognition, cell docking, etc.). For example, components of the glycocalyx of neutrophils dock onto endothelial membrane proteins, called selectins ( p. 94). The cytoskeleton allows the cell to maintain and change its shape (during cell division, etc.), make selective movements (migration, cilia), and conduct intracellular transport activities (vesicle, mitosis). It contains actin filaments as well as microtubules and intermediate filaments (e.g., vimentin and desmin filaments, neurofilaments, keratin filaments) that extend from the centrosome. The Cell (continued) Tubular proteinuria, toxicity of lipophilic substances, immune deficiency
Plate 1.7 The Cell IV 15 G. Cell membrane Extracellular Lipid molecule membrane protein Glycoprotein Glycolipid Glycocalyx Cytosol membrane Membrane constituents 2 Multiple membrane- acids 4 Membrane lipids
151 Fundamentals and Cell Physiology Plate 1.7 The Cell IV & % % & % <% " " "7 & " % " % & & A " " %& . % % % % " " % "% & 37 & % " % % " #7 % & = % % <%% <% & " 1 0!&
16 Transport In, Through and Between Cells The lipophilic cell membrane protects the cell can be pumped from the cytosol into the Er by interior from the extracellular fluid, which has a Ca-ATPase called SERCA (sarcoplasmic en- completely different composition(p 2). doplasmic reticulum Ca2*-transporting This is imperative for the creation and main- ATPase). The resulting Ca2- stores can be re- enance of a cell s internal environment by leased into the cytosol via a Ca channel(ry- neans of metabolic energy expenditure. Chan- anodine receptor, RyR)in response to a trigger els(pores). carriers, ion pur membrane con- E transmembrane transport of selected sub- tains large pores called porins that render it ances. This includes the import and export of permeable to small molecules (<5 kDa), and metabolic substrates and metabolites and the the inner membrane has high concentrations lective transport of ions used to create or of specific and enzymes(→B Enzyme complexes of the respiratory chain an essential role in excitability of nerve and transfer electrons(e")from high to low energy muscle cells. In addition, the effects of sub- levels, thereby pumping H* ions from the tances that readily penetrate the cell mem- matrix space into the intermembral rane in most cases(e.g, water and CO2)can of a litigated by selectively transporting certain gradient directed into the matrix. This not only her substances. This allows the cell to com- drives ATP synthetase(ATP production: -B2). ensate for undesirable changes in the cell but also promotes the inflow of pyruvate"and plume or pH of the cell interior. and p. 28). Ca+ions that regulate Ca2'-sensi Intracellular Transport tive mitochondrial enzymes in muscle tissue The cell interior is divided into different com- can b vith atp rements by the organelle membranes In expenditure( B2) thereby allowing the mi- me cases, very broad intracellular spaces tochondria to form a sort of Ca* buffer space must be crossed during transport. For this pur- for protection against dangerously high co pose, a variety of specific intracellular trans- centrations of Ca" in the cytosol. The inside. Nuclea the nuclear lease)drives the uptake of ADP3-in exchange vide the channels for RNA export( u- for ATP-(potential-driven transport;-B2a and p. 22). Protein transport from the plasmic reticulum to the Golgi complex Transport between Adjacent Cells Axonal transport in the nerve fibers, in occurs either via diffusion through the extra- which distances of up to 1 meter can be cellular space(e. g, pa hormone effects) crossed (p 42) These transport processes he filaments of the ons)located within a so-called gap cytoskeleton. Example: while expending ATP, junction or nexus (C). A connexon is a hem he microtubules set dynein-bound vesicles in channel formed by six connexin molecules motion in the one direction, and kinesin- (C2). One connexon docks with another con- bound vesicles in the other (p 13 F). on on an adjacent cell, thereby forming Main sites of Intracellular Transmembrane common channel through which substanc with molecular masses of up to around 1 kDa Lysosomes: Uptake of H"ions from the cyto- can pass. Since this applies not only for ions and release of metabolites such as amino such as Ca but also for a number of organic substances such as ATP, these types of cells are Endoplasmic reticulum(ER): In addition to a united to form a close electrical and metabolic translocator protein(p. 10), the ER has two unit (syncytium), as is present in the her proteins that transport Ca*(A). Ca- epithelium, many smooth muscles (single-P
161 Fundamentals and Cell Physiology The lipophilic cell membrane protects the cell interior from the extracellular fluid, which has a completely different composition ( p. 2). This is imperative for the creation and maintenance of a cell’s internal environment by means of metabolic energy expenditure. Channels (pores), carriers, ion pumps ( p. 26ff.) and the process of cytosis ( p. 28) allow transmembrane transport of selected substances. This includes the import and export of metabolic substrates and metabolites and the selective transport of ions used to create or modify the cell potential ( p. 32), which plays an essential role in excitability of nerve and muscle cells. In addition, the effects of substances that readily penetrate the cell membrane in most cases (e.g., water and CO2) can be mitigated by selectively transporting certain other substances. This allows the cell to compensate for undesirable changes in the cell volume or pH of the cell interior. Intracellular Transport The cell interior is divided into different compartments by the organelle membranes. In some cases, very broad intracellular spaces must be crossed during transport. For this purpose, a variety of specific intracellular transport mechanisms exist, for example: ◆ Nuclear pores in the nuclear envelope provide the channels for RNA export out of the nucleus and protein import into it ( p. 11 C); ◆ Protein transport from the rough endoplasmic reticulum to the Golgi complex ( p. 13 F); ◆ Axonal transport in the nerve fibers, in which distances of up to 1 meter can be crossed (p. 42). These transport processes mainly take place along the filaments of the cytoskeleton. Example: while expending ATP, the microtubules set dynein-bound vesicles in motion in the one direction, and kinesinbound vesicles in the other ( p. 13 F). Main sites of Intracellular Transmembrane Transport are: ◆ Lysosomes: Uptake of H+ ions from the cytosol and release of metabolites such as amino acids into the cytosol ( p. 12); ◆ Endoplasmic reticulum (ER): In addition to a translocator protein ( p. 10), the ER has two other proteins that transport Ca2+ ( A). Ca2+ can be pumped from the cytosol into the ER by a Ca2+-ATPase called SERCA (sarcoplasmic endoplasmic reticulum Ca2+-transporting ATPase). The resulting Ca2+ stores can be released into the cytosol via a Ca2+ channel (ryanodine receptor, RyR) in response to a triggering signal ( p. 36). ◆ Mitochondria: The outer membrane contains large pores called porins that render it permeable to small molecules ( 5 kDa), and the inner membrane has high concentrations of specific carriers and enzymes ( B). Enzyme complexes of the respiratory chain transfer electrons (e–) from high to low energy levels, thereby pumping H+ ions from the matrix space into the intermembrane space ( B1), resulting in the formation of an H+ ion gradient directed into the matrix. This not only drives ATP synthetase (ATP production; B2), but also promotes the inflow of pyruvate– and anorganic phosphate, Pi – (symport; B2b,c and p. 28). Ca2+ ions that regulate Ca2+-sensitive mitochondrial enzymes in muscle tissue can be pumped into the matrix space with ATP expenditure ( B2), thereby allowing the mitochondria to form a sort of Ca2+ buffer space for protection against dangerously high concentrations of Ca2+ in the cytosol. The insidenegative membrane potential (caused by H+ release) drives the uptake of ADP3 – in exchange for ATP4 – (potential-driven transport; B2a and p. 22). Transport between Adjacent Cells In the body, transport between adjacent cells occurs either via diffusion through the extracellular space (e.g., paracrine hormone effects) or through channel-like connecting structures (connexons) located within a so-called gap junction or nexus ( C). A connexon is a hemichannel formed by six connexin molecules ( C2). One connexon docks with another connexon on an adjacent cell, thereby forming a common channel through which substances with molecular masses of up to around 1 kDa can pass. Since this applies not only for ions such as Ca2+, but also for a number of organic substances such as ATP, these types of cells are united to form a close electrical and metabolic unit (syncytium), as is present in the epithelium, many smooth muscles (singleTransport In, Through and Between Cells Ischemia, storage diseases, neural regeneration
Plate 1.8 Transport In, Through and Between Cells I17 A Ca" transport through the ER membrane Ca2*-ATPase Ca2+ channel hormon, etc.) E5 105<(10-5)mo B Mitochondrial transport inner membrane Ribosomes Granules Formation of H gradie H' gradient driving ATP synthesis and carriers NADH+H' Matrix of respiratory chain Poring
171 Fundamentals and Cell Physiology Plate 1.8 Transport In, Through and Between Cells I (6 +(CC +(C # C CD C(/# (/# (60# " # " # C C C C C C C C C (60# C C C C C & &) %+ C & & #4 -.#1 -.#4 E -.#1 -.#4 E * % F * - &&! &&! &&! ' @F" % % " &&! ' & (6 " " ! # C=(6 ( 54 54 1$ 8& (6 " !& #4 !
18 Transport In, Through and Between Cells(continued) unit type, -p 70), the myocardium, and exterior)of an epithelial cell has a different set the glia of the central system Electric of transport proteins from the basolatero coupling permits the transfer of excitation, membrane(facing the blood). So called tight g, from excited muscle cells to their adjacen Inctions(zonulae occludentes), at which the ells are held together, prevent mixing of the citation across wide regions of an organ, such two membrane types( D2). n ureter, atrium, and ventricles of the heart, but lar barriers also permit paracellular transport na and CNS also communicate in this man- epithelia(e.g, in the small intestinal and pre in the glia mal renal tubules)are relatively permeable to p. 344)and epithelia help to distribute the small molecules(leaky ) whereas others are less leaky The 2 and barrier activities( see below) throughout degree of permeability depends on the the entire cell community. However, the con- strength of the tight junctions and the types of nexon close when the concentration of Ca2- proteins contained within: occludins, JAM (in an extreme case, due to a hole in cell mem- n adhesion molecule. claudins. So ane)or H concentration increases too 16 claudins are known to determine the pidly (C3). In other words, the individual specific permeability: for example intact fective)cell is left to deal with its own prob- claudin 16 is required for the paracellular re lems when necessary to preserve the function- sorption of Mg -in the Henle's loop section of ality of the cell communi he renal tubule (p 180). The paracellular path and the degree of its permeability(for e ple cationic or anionic specificity )are es- In single cells, the cell membrane is re- sential functional elements of the various ponsible for separating the"interior"from epithelia Macromolecules can cross the bar- he"exterior "In the multicellular organism, rier formed by the endothelium of the vessel th its larger compartments, cell layers pro- wall by transcytosis (p. 28), yet paracellular vide this function. The epithelia of skin and transport also plays an essential role, es- gastrointestinal, urogenital and respiratory pecially in the fenestrated endothelium. tracts, the endothelia of blood vessels and Anionic macromolecules like albumin. which glia are examples of this type of extensive must remain in the bloodstream because of its er. They separate the immediate extra- colloid osmotic action(p. 210), are held back ellular space from other spaces that narges at the intercellular spaces tly different in composition, e.g., those and, in some cases, at the fenestra. lled with air (skin, bronchial epithelia), Long-distance transport between gastrointestinal contents, bile various organs of the body and between the tubules, urinary bladder, gallbladder). body and the outside world is also necessary ueous humor of the eye, blood (endothelia) Convection is the most important transpo d cerebrospinal fluid(blood-cerebrospinal mechanism involved in long-distance trans- luid barrier), and from the extracellular space port (p. 24). of the CNS(blood-brain barrier ). Nonetheless, through these cell layers. This requires se tive transcellular transport with import into the cell followed by export from the cell. Un like cells with a completely uniform plasma ne(e.g, blood cells), epi- and en- dothelial cells are polar cells, their Ire (p 9A and B)and transport function. Hence, the apical membrane( facing
181 Fundamentals and Cell Physiology unit type, p. 70), the myocardium, and the glia of the central nervous system. Electric coupling permits the transfer of excitation, e.g., from excited muscle cells to their adjacent cells, making it possible to trigger a wave of excitation across wide regions of an organ, such as the stomach, intestine, biliary tract, uterus, ureter, atrium, and ventricles of the heart, but not skeletal muscles. Certain neurons of the retina and CNS also communicate in this manner (electric synapses). Gap junctions in the glia ( p. 344) and epithelia help to distribute the stresses that occur in the course of transport and barrier activities (see below) throughout the entire cell community. However, the connexons close when the concentration of Ca2+ (in an extreme case, due to a hole in cell membrane) or H+ concentration increases too rapidly ( C3). In other words, the individual (defective) cell is left to deal with its own problems when necessary to preserve the functionality of the cell community. Transport through Cell Layers In single cells, the cell membrane is responsible for separating the “interior” from the “exterior.” In the multicellular organism, with its larger compartments, cell layers provide this function. The epithelia of skin and gastrointestinal, urogenital and respiratory tracts, the endothelia of blood vessels, and neuroglia are examples of this type of extensive barrier. They separate the immediate extracellular space from other spaces that are greatly different in composition, e.g., those filled with air (skin, bronchial epithelia), gastrointestinal contents, urine or bile (tubules, urinary bladder, gallbladder), aqueous humor of the eye, blood (endothelia) and cerebrospinal fluid (blood–cerebrospinal fluid barrier), and from the extracellular space of the CNS (blood–brain barrier). Nonetheless, certain substances must be able to pass through these cell layers. This requires selective transcellular transport with import into the cell followed by export from the cell. Unlike cells with a completely uniform plasma membrane (e.g., blood cells), epi- and endothelial cells are polar cells, as defined by their structure (p. 9A and B) and transport function. Hence, the apical membrane (facing exterior) of an epithelial cell has a different set of transport proteins from the basolateral membrane (facing the blood). So called tight junctions (zonulae occludentes), at which the cells are held together, prevent mixing of the two membrane types ( D2). In addition to transcellular transport, cellular barriers also permit paracellular transport which takes place between cells. Certain epithelia (e.g., in the small intestinal and proximal renal tubules) are relatively permeable to small molecules (leaky), whereas others are less leaky (e.g., distal nephron, colon). The degree of permeability depends on the strength of the tight junctions and the types of proteins contained within: occludins, JAM [junction adhesion molecule], claudins. So far 16 claudins are known to determine the specific permeability: for example intact claudin 16 is required for the paracellular resorption of Mg2 – in the Henle’s loop section of the renal tubule (p. 180). The paracellular path and the degree of its permeability (for example cationic or anionic specificity) are essential functional elements of the various epithelia. Macromolecules can cross the barrier formed by the endothelium of the vessel wall by transcytosis ( p. 28), yet paracellular transport also plays an essential role, especially in the fenestrated endothelium. Anionic macromolecules like albumin, which must remain in the bloodstream because of its colloid osmotic action ( p. 210), are held back by the wall charges at the intercellular spaces and, in some cases, at the fenestra. Long-distance transport between the various organs of the body and between the body and the outside world is also necessary. Convection is the most important transport mechanism involved in long-distance transport ( p. 24). Transport In, Through and Between Cells (continued) Inflammation and irritation of skin and mucosa, meningitis