Chapter 1 General Physiologic Processes 15 Pore Selectivity filter Cytosol Gate The upper rangement of the identical subunits around a central pore, each subunit ting of six me brane-spanning domains, S1 to S6. A selectivity filter (about 0.3 nm in d ) is formed by extracellular loops, each between S5 and S6 of the corresponding subunit This"P loop"of about O amino acids folds and doubles back partway into the central pore region. A voltage-sensi ve domain(S4) is indicated by the"+"sign in this view. The lower portion shows tional view of two subunits so as to suggest the central pore and the selectivity filter. A gating echanism, linked to the voltage-sensitive domain, is also indicated. This is sometimes caller m-gate. The cytoplasmic region of the channel includes a ball-and-chain for channel inactivation (h-gate", such as would be obse is, therefore, called a"hinged lid. " Ca*channels have inactivation mechanisms that depend ee of openness of the h-gates, even in fully repolarized cells, depen men al. For that reason, the rate and extent of depolarization in excitable cells are maller if the resting membrane potential is less negative A channel that is in the open state allows current to flow. A channel is inactivated when it conducts no ion flow, even though its gating stimulus continues to be present. An inactivated channel must recover from inactivation and be brought to the closed state before it n be opened again. Inactivation is a process by which a cytoplasmic portion of the channel occludes the inner pore region(see Figure 1-6 Ion channel selectivity is primarily bestowed by the presence of specific mino acid motifs in the region of the selectivity filter. For example, the motif
• A channel that is in the open state allows current to flow. • A channel is inactivated when it conducts no ion flow, even though its gating stimulus continues to be present. An inactivated channel must recover from inactivation and be brought to the closed state before it can be opened again. Inactivation is a process by which a cytoplasmic portion of the channel occludes the inner pore region (see Figure 1–6). Ion channel selectivity is primarily bestowed by the presence of specific amino acid motifs in the region of the selectivity filter. For example, the motif Chapter 1 General Physiologic Processes 15 S1 S2 S3 S5 S6 Pore Selectivity filter Extracellular space Gate Inactivation particle Cytosol Figure 1–6 Schematic of a typical ion channel. The upper portion shows the tetrameric arrangement of the identical subunits around a central pore, each subunit consisting of six membrane-spanning domains, S1 to S6. A selectivity filter (about 0.3 nm in diameter) is formed by extracellular loops, each between S5 and S6 of the corresponding subunit. This “P loop” of about 20 amino acids folds and doubles back partway into the central pore region. A voltage-sensitive domain (S4) is indicated by the “+” sign in this view. The lower portion shows a cross-sectional view of two subunits so as to suggest the central pore and the selectivity filter. A gating mechanism, linked to the voltage-sensitive domain, is also indicated. This is sometimes called the “m-gate.” The cytoplasmic region of the channel includes a “ball-and-chain” mechanism for channel inactivation (“h-gate”), such as would be observed in voltage-gated channels for K+ . In the Na+ channels, the mechanism is formed by a smaller loop, attached at both ends, and is, therefore, called a “hinged lid.” Ca++ channels have inactivation mechanisms that depend on several regions. (The degree of openness of the h-gates, even in fully repolarized cells, depends on membrane potential. For that reason, the rate and extent of depolarization in excitable cells are smaller if the resting membrane potential is less negative.)
PDQ PHYSIOLOGY GYG(glycine, tyrosine, glycine)is found in all but one of the single-pore K+ channels cloned to date; the motif DEKA(aspartate, glutamate, lysine, alanine) is found in Na* channels; and E(glutamate)is found in Ca** channels. Cell Environment A large portion of tissue volume is occupied by the extracellular space. This is a complex arrangement of unconjugated proteins, glycoconjugate pro teins,and glycosaminoglycans, all forming a structured network, named the extracellular matrix. Its physical composition is that two types of uncon jugated proteins(collagen and elastin) are embedded in a hydrated poly- saccharide gel, named ground substance. Collagen and elastin can be visu- alized as reinforcing rods that are embedded in the ground substance, much like structural steel rods are embedded in concret Collagen Collagen constitutes about 25% of the proteins in the human body, and this makes it the most common of proteins. It is a structural protein and con sists of three left-handed helical polypeptide chains, individually named the pro-a-chains, wound around one another along the long axis in a righ handed superhelix. Each a-chain is encoded by a single gene and consists of about 1,000 amino acids. Twenty-five different a-chains have been identi fied, and they differ in their relative contents of amino acids versus the amino acid proline or its hydroxylated derivative hydroxyproline(Figure 1-7) Hydroxyproline and hydroxylysine are found only in collagen. They are formed from their respective parent by proline hydroxylase or lysine hydrox ylase, both of which require vitamin C for their action. Lack of vitamin C brings on the complex of connective tissue disease known as scurvy The steric conformation of individual amino acids is of crucial impor tance to the helix conformation, and point mutations affecting only one mino acid can have profound consequences and result in hereditary dis- orders of connective tissue. Thus, if glycine, which occupies every third position in the amino acid sequence and has only a single H-atom side chain, is replaced by cysteine, whose side chain is a CH2-SH, the outcome is osteogenesis imperfecta, a condition that is characterized by hearing loss d fragility of bone and blood vessel Collagens differ with respect to chain composition, and the 16 nake up the family are grouped according to the shape of their aggregates. Fibril-forming collagens. These include types I, I L, Ill, V, and XI. Type I is the most abundant form of collagen and is found in skin, bone tendons ligaments, and the cornea. Types III and V are found in blood vessel walls
GYG (glycine, tyrosine, glycine) is found in all but one of the single-pore K+ channels cloned to date; the motif DEKA (aspartate, glutamate, lysine, alanine) is found in Na+ channels; and E (glutamate) is found in Ca++ channels. Cell Environment A large portion of tissue volume is occupied by the extracellular space. This is a complex arrangement of unconjugated proteins, glycoconjugated proteins, and glycosaminoglycans, all forming a structured network, named the extracellular matrix. Its physical composition is that two types of unconjugated proteins (collagen and elastin) are embedded in a hydrated polysaccharide gel, named ground substance. Collagen and elastin can be visualized as reinforcing rods that are embedded in the ground substance, much like structural steel rods are embedded in concrete. Collagen Collagen constitutes about 25% of the proteins in the human body, and this makes it the most common of proteins. It is a structural protein and consists of three left-handed helical polypeptide chains, individually named the pro-α-chains, wound around one another along the long axis in a righthanded superhelix. Each α-chain is encoded by a single gene and consists of about 1,000 amino acids. Twenty-five different α-chains have been identi- fied, and they differ in their relative contents of amino acids versus the amino acid proline or its hydroxylated derivative hydroxyproline (Figure 1–7). Hydroxyproline and hydroxylysine are found only in collagen. They are formed from their respective parent by proline hydroxylase or lysine hydroxylase, both of which require vitamin C for their action. Lack of vitamin C brings on the complex of connective tissue disease known as scurvy. The steric conformation of individual amino acids is of crucial importance to the helix conformation, and point mutations affecting only one amino acid can have profound consequences and result in hereditary disorders of connective tissue. Thus, if glycine, which occupies every third position in the amino acid sequence and has only a single H-atom side chain, is replaced by cysteine, whose side chain is a CH2–SH, the outcome is osteogenesis imperfecta, a condition that is characterized by hearing loss and fragility of bone and blood vessels. Collagens differ with respect to chain composition, and the 16 types that make up the family are grouped according to the shape of their aggregates. Fibril-forming collagens. These include types I, II, III, V, and XI. Type I is the most abundant form of collagen and is found in skin, bone, tendons, ligaments, and the cornea. Types III and V are found in blood vessel walls. 16 PDQ PHYSIOLOGY
Chapter 1 General Physiologic Processes Proline or Hydroxyproline 67 nm Figure 1-7 Structure of collagen. A, Section of one left-handed helical a-chain showing the typical glycine-proline/hydroxyproline-X motif. B, The assembled right-handed helix of 3 a- chains that constitute a single collagen molecule. The h side chain of glycine in each chain faces into the center of the triple-stranded helix. Each strand is 350 repeats of the glycine-proline-X motif. C, Type I collagen is characterized by fibrils composed of a staggered, linear arrangement nal of a neighbor. Other types of collagen show different molecular arrangements and linkages. The others contribute to the interstitial supporting structures in cartilage intervertebral discs, gut, and bone Fibril-associated collagens. These include types IX, XIl, XIV, and XVI A structural feature of this group is an interrupted triple helix. They are attached to the surface of the collagen fibrils and provide links between the fibrils and between the fibril and the extracellular matrix. They are found mostly in skin, tendon, and cartilage. Mesh-forming collagens(nonfibrillar collagens). These include types IV, VI, VIL, VIlL,X, and XIll. They arrange themselves in multilayered networks of sheet-like meshes. Type IV dominates in basement membranes, type VIII is found in the vascular endothelium, type X in the calcifying artilage, and type XIlI in a variety of tissues
The others contribute to the interstitial supporting structures in cartilage, intervertebral discs, gut, and bone. Fibril-associated collagens. These include types IX, XII, XIV, and XVI. A structural feature of this group is an interrupted triple helix. They are attached to the surface of the collagen fibrils and provide links between the fibrils and between the fibril and the extracellular matrix. They are found mostly in skin, tendon, and cartilage. Mesh-forming collagens (nonfibrillar collagens). These include types IV, VI, VII, VIII, X, and XIII. They arrange themselves in multilayered networks of sheet-like meshes. Type IV dominates in basement membranes, type VIII is found in the vascular endothelium, type X in the calcifying cartilage, and type XIII in a variety of tissues. Chapter 1 General Physiologic Processes 17 Glycine Proline or Hydroxyproline X A) B) C) 67 nm 35 nm 300 nm Figure 1–7 Structure of collagen. A, Section of one left-handed helical -chain showing the typical glycine-proline/hydroxyproline-X motif. B, The assembled right-handed helix of 3 - chains that constitute a single collagen molecule. The H side chain of glycine in each chain faces into the center of the triple-stranded helix. Each strand is 350 repeats of the glycine-proline-X motif. C, Type I collagen is characterized by fibrils composed of a staggered, linear arrangement of collagen molecules, the N terminal of one molecule being linked covalently to the C terminal of a neighbor. Other types of collagen show different molecular arrangements and linkages. X = any amino acid
PDQ PHYSIOLOGY Except for bone, in which collagen is very strongly cross-linked, the molecular chains of collagen are not generally so interconnected. However, with increasing age, such cross-connections appear, and the result is loss of pliability and a more "leathery"appearance of skin. Elastin Elastin is an elastic protein. It can be stretched without tearing, and when it is released from the stretched state, it will recoil quickly to its original state. It is found wherever elastic properties are required, but it also contains amino acid sequences that are chemotactic for fibroblasts and monocytes. Elastin exists as an amorphous, extensively cross-linked, coiled structure, and these covalent desmosine and isodesmosine cross-linkages bestow elas- tic behavior. When elastin molecules aggregate to form elastic fibers, then the amorphous elastin core of the fiber is surrounded by a sheath of fibrillin, a large glycoprotein that is secreted by fibroblasts and smooth muscle cells Ground substance Ground substance consists partly of structural elements(glycoproteins) and partly of hydrated gel that is formed by glycosaminoglycans and gl cosaminoglycans covalently linked to a protein backbone(proteoglycans) Glycoproteins. This group includes fibronectin, laminin, vitronectin, tenascin, fibrillin, entactin, and several more. Their ton is to provide scaffolding or adhesion. They do this by establishing contacts between the cellular or macromolecular components of the extracellular matrix or between the matrix and the outside of cells Cell surface receptors and adhesion molecules. Both classes of molecules re required for the interaction of cells with matrix elements as well as with other cells. Two important families of glycoproteins providing such func tions are the integrins and the cadherins. also involved are a variety of cellular adhesion molecules(CAM), such as NCAM (neu- ral-), ICAM(intercellular-), VCAM(vascular-), and myelin-associated glycoprotein(MAG) CD44, the principal cell surface receptor for hyaluronic acid(hyaluro- nan);and laminin-binding protein. Integrins: This large family of cell surface glycoproteins functions as(1) receptors for almost all glycoproteins of the extracellular matrix, (2)cell- to-cell adhesion molecules, and (3)transmembrane signal linkers. The lat
Except for bone, in which collagen is very strongly cross-linked, the molecular chains of collagen are not generally so interconnected. However, with increasing age, such cross-connections appear, and the result is loss of pliability and a more “leathery” appearance of skin. Elastin Elastin is an elastic protein. It can be stretched without tearing, and when it is released from the stretched state, it will recoil quickly to its original state. It is found wherever elastic properties are required, but it also contains amino acid sequences that are chemotactic for fibroblasts and monocytes. Elastin exists as an amorphous, extensively cross-linked, coiled structure, and these covalent desmosine and isodesmosine cross-linkages bestow elastic behavior. When elastin molecules aggregate to form elastic fibers, then the amorphous elastin core of the fiber is surrounded by a sheath of fibrillin, a large glycoprotein that is secreted by fibroblasts and smooth muscle cells. Ground Substance Ground substance consists partly of structural elements (glycoproteins) and partly of hydrated gel that is formed by glycosaminoglycans and glycosaminoglycans covalently linked to a protein backbone (proteoglycans). Glycoproteins. This group includes fibronectin, laminin, vitronectin, tenascin, fibrillin, entactin, and several more. Their main function is to provide scaffolding or adhesion. They do this by establishing contacts between the cellular or macromolecular components of the extracellular matrix or between the matrix and the outside of cells. Cell surface receptors and adhesion molecules. Both classes of molecules are required for the interaction of cells with matrix elements as well as with other cells. Two important families of glycoproteins providing such functions are the integrins and the cadherins. Also involved are • a variety of cellular adhesion molecules (CAM), such as NCAM (neural-), ICAM (intercellular-), VCAM (vascular-), and myelin-associated glycoprotein (MAG); • CD44, the principal cell surface receptor for hyaluronic acid (hyaluronan); and • laminin-binding protein. Integrins: This large family of cell surface glycoproteins functions as (1) receptors for almost all glycoproteins of the extracellular matrix, (2) cellto-cell adhesion molecules, and (3) transmembrane signal linkers. The lat- 18 PDQ PHYSIOLOGY
Chapter 1 General Physiologic Processes ter function is possible because a typical integrin molecule will bind to fibronectin on the outside of the cell and to the actin cytoskeleton inside the cell Cadherins: These are cell-to-cell adhesion glycoproteins that function only in the presence of Cat+. They consist of a large extracellular domain a single transmembrane domain, and a short cytoplasmic domain. The cytoplasmic portion is closely associated with cytoskeletal elements by way of the catenins in a region that is histologically identified as a desmosom in anchoring junctions. The cadherins are of particular importance during development but are expressed in adults in the epithelial cells, nervous tissue, and muscle. One of their roles in development is that cell types expressing specific cadherins collect in groups so that particular cells occupy particular locations Glycosaminoglycans. The glycosaminoglycans are unbranched polysaccharide chains consisting of disaccharide repeats Each disaccharide is made up of two types of monosaccharides arranged in an alternating fashion. The glycosaminoglycans tend to exist as gels at body temperature Their high density of negative charges binds clouds of ions whose osmotic activity attracts and holds water in the extracellular matrix. Six glycosaminoglycans are found in human tissue(Figure 1-8):(1) hyaluronic acid(hyaluronan);(2)chondroitin 4-sulfate; ( 3)dermatan sul- fate;(4)heparan sulfate;(5)heparin, and (6)keratan sulfate. Except for hyaluronic acid, they all attach themselves to a core protein to form pro teoglycans Proteoglycans. The glycosaminoglycans other than hyaluronic acid arrange themselves around one of many core proteins. These include perlican, lumican, fibroglycan, versican, and several more. The main functions of proteoglycans are mechanical support for cells modulation of extracellular diffusion, enzyme activity, and growth factors: and adulation of cell adhesion, motility, and proliferation CELL NOURISHMENT AND GROWTH Energy Metabolism Maintenance of cell functions requires energy, and most human cells derive this energy by hydrolysis of ATP(adenosine 5-triphosphate), which yield ADP +P+30.5 k] of energy per mole of ATP
ter function is possible because a typical integrin molecule will bind to fibronectin on the outside of the cell and to the actin cytoskeleton inside the cell. Cadherins: These are cell-to-cell adhesion glycoproteins that function only in the presence of Ca++. They consist of a large extracellular domain, a single transmembrane domain, and a short cytoplasmic domain. The cytoplasmic portion is closely associated with cytoskeletal elements by way of the catenins in a region that is histologically identified as a desmosome in anchoring junctions. The cadherins are of particular importance during development but are expressed in adults in the epithelial cells, nervous tissue, and muscle. One of their roles in development is that cell types expressing specific cadherins collect in groups so that particular cells occupy particular locations. Glycosaminoglycans. The glycosaminoglycans are unbranched polysaccharide chains consisting of disaccharide repeats. Each disaccharide is made up of two types of monosaccharides arranged in an alternating fashion. The glycosaminoglycans tend to exist as gels at body temperature. Their high density of negative charges binds clouds of ions whose osmotic activity attracts and holds water in the extracellular matrix. Six glycosaminoglycans are found in human tissue (Figure 1–8): (1) hyaluronic acid (hyaluronan); (2) chondroitin 4-sulfate; (3) dermatan sulfate; (4) heparan sulfate; (5) heparin, and (6) keratan sulfate. Except for hyaluronic acid, they all attach themselves to a core protein to form proteoglycans. Proteoglycans. The glycosaminoglycans other than hyaluronic acid arrange themselves around one of many core proteins. These include perlican, lumican, fibroglycan, versican, and several more. The main functions of proteoglycans are • mechanical support for cells; • modulation of extracellular diffusion, enzyme activity, and growth factors; and • modulation of cell adhesion, motility, and proliferation. CELL NOURISHMENT AND GROWTH Energy Metabolism Maintenance of cell functions requires energy, and most human cells derive this energy by hydrolysis of ATP (adenosine 5'-triphosphate), which yields ADP + P + 30.5 kJ of energy per mole of ATP. Chapter 1 General Physiologic Processes 19