PDQ PHYSIOLOGY charged, phosphorylated head group and two hydrocarbon tails. Only one of the tails is a fatty acid; the other one is formed by sphingosine. The most common sphingolipid is sphingomyelin, and it is abundant in the myelin sheath that surrounds many axons Membrane phospholipids are cleaved by specific phospholipases(see Figure 1-5). Thus, phospholipase A2 yields arachidonic acid, and phos- pholipase C yields dAG plus the(head and phosphate)grouping(see Cholesterol. The cholesterol molecule contains a steroid ring, which is a structure of physical rigidity. As a result, the presence of cholesterol at a fairly high concentration(20 g per 100 g of lipid) in the phospholipid bilayer of the plasma membrane reduces membrane fluidity and makes it more difficult for molecules to force their way through the membrane. The number of cholesterol molecules is equal in the two leaves of the bilayer Proteins. The plasma membrane of many cells contains a high fraction of proteins, and they are responsible for many biologic functions of the plasma membrane. The proteins either are attached to just one side of the bilayer(=peripheral proteinsor penetrate through the bilayer(= integral proteins). Integral proteins span the membrane only once or several times, each membrane-spanning domain being serially linked to its neighbor by a loop that may be intra-or extracellular. They function as channels, carriers, enzymes, or signal transducers, as detailed elsewhere Phospholipase Al Phospholipase Az Phospholipase C Arachidonic acid- Diacylglycerol(DAG) Figure 1-5 Specific sites of action of different phospholipases. Also shown is the kinking effect of a double bond in one of the fatty
Sphingolipids. The sphingolipids, like the glycero-phospholipids, have a charged, phosphorylated head group and two hydrocarbon tails. Only one of the tails is a fatty acid; the other one is formed by sphingosine. The most common sphingolipid is sphingomyelin, and it is abundant in the myelin sheath that surrounds many axons. Membrane phospholipids are cleaved by specific phospholipases (see Figure 1–5). Thus, phospholipase A2 yields arachidonic acid, and phospholipase C yields DAG plus the (head and phosphate) grouping (see Figure 1–5). Cholesterol. The cholesterol molecule contains a steroid ring, which is a structure of physical rigidity. As a result, the presence of cholesterol at a fairly high concentration (20 g per 100 g of lipid) in the phospholipid bilayer of the plasma membrane reduces membrane fluidity and makes it more difficult for molecules to force their way through the membrane. The number of cholesterol molecules is equal in the two leaves of the bilayer. Proteins. The plasma membrane of many cells contains a high fraction of proteins, and they are responsible for many biologic functions of the plasma membrane. The proteins either are attached to just one side of the bilayer (= peripheral proteins) or penetrate through the bilayer (= integral proteins). Integral proteins span the membrane only once or several times, each membrane-spanning domain being serially linked to its neighbor by a loop that may be intra- or extracellular. They function as channels, carriers, enzymes, or signal transducers, as detailed elsewhere. 10 PDQ PHYSIOLOGY O O O O CH2 CH H2C O P O O- O HEAD Glycerol Phosphate group Phospholipase A1 Phospholipase A2 Phospholipase C Phospholipase D Diacylglycerol (DAG) C CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH3 C CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH3 CH CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 Arachidonic acid Figure 1–5 Specific sites of action of different phospholipases. Also shown is the kinking effect of a double bond in one of the fatty acid tails
Chapter 1 General Physiologic Processes Membrane carbohydrates. Some plasma membrane proteins are heavily glycosylated, with carbohydrate chains as long as 100 units and facing only the extracellular region. Such protein-carbohydrate combinations are named proteoglycans, and they form a dense covering, the glycocalyx This covering offers mechanical and chemical protection, participates in cell-to-cell recognition, and plays a role in cell-to-cell adhesion. Membrane function Membrane transport mechanisms. The plasma membrane separates the cytosol from extracellular space and maintains the highly unequal ion concentrations of the two spaces. This is accomplished by four membrane transport strategies Macromolecules, such as proteins, are transported in carrier vesicles either out of the cell(exocytosis)or into the cell(endocytosis) Gases and lipid-soluble molecules cross the membrane by diffusion through the lipid phase and are driven down their concentration gradients Some ions and selected nonionic substances are transported by specific protein carriers by processes that are classified as active or passive transport mechanisms, depending on whether metabolic energy is directly and stoichiometrically applied to run the process(Table 1-2) Some ions move through protein channels that can be exquisitely elective in what ion(s) they will accept. The conductance of such channels can be varied so that they offer a mechanism of changing embrane permeability. The driving force for ion transport is the elec- trochemical gradient of the ion. Active transport. Transport is active when it is tightly coupled to a source of metabolic energy, usually the stoichiometric hydrolysis of ATP. It occurs in only one direction across the plasma membrane and generally transports ubstances against their electrochemical gradient and by means of a specifi carrier Primary active transport utilizes atP directly. condary active transport has an absolute requirement for the simul Is movement of an ion(generally Na*) down a concentration gra- dient that was created by primary transporters For example, the Na'-K' pump requires one ATP molecule to be hydrolyzed for every Pump, moving 3Na* out of th and 2K+ in
Membrane carbohydrates. Some plasma membrane proteins are heavily glycosylated, with carbohydrate chains as long as 100 units and facing only the extracellular region. Such protein–carbohydrate combinations are named proteoglycans, and they form a dense covering, the glycocalyx. This covering offers mechanical and chemical protection, participates in cell-to-cell recognition, and plays a role in cell-to-cell adhesion. Membrane Function Membrane transport mechanisms. The plasma membrane separates the cytosol from extracellular space and maintains the highly unequal ion concentrations of the two spaces. This is accomplished by four membrane transport strategies: • Macromolecules, such as proteins, are transported in carrier vesicles either out of the cell (exocytosis) or into the cell (endocytosis). • Gases and lipid-soluble molecules cross the membrane by diffusion through the lipid phase and are driven down their concentration gradients. • Some ions and selected nonionic substances are transported by specific protein carriers by processes that are classified as active or passive transport mechanisms, depending on whether metabolic energy is directly and stoichiometrically applied to run the process (Table 1–2). • Some ions move through protein channels that can be exquisitely selective in what ion(s) they will accept. The conductance of such channels can be varied so that they offer a mechanism of changing membrane permeability. The driving force for ion transport is the electrochemical gradient of the ion. Active transport. Transport is active when it is tightly coupled to a source of metabolic energy, usually the stoichiometric hydrolysis of ATP.† It occurs in only one direction across the plasma membrane and generally transports substances against their electrochemical gradient and by means of a specific carrier. • Primary active transport utilizes ATP directly. • Secondary active transport has an absolute requirement for the simultaneous movement of an ion (generally Na+) down a concentration gradient that was created by primary transporters. Chapter 1 General Physiologic Processes 11 †For example, the Na+–K+ pump requires one ATP molecule to be hydrolyzed for every turn of the pump, moving 3Na+ out of the cell and 2K+ in
PDQ PHYSIOLOGY Table 1-2 Membrane Transport Mechanisms Class Subclasses Primary Active Metabolic energy is applied directly d stoichiometrically to accomplish transport AGAINST an electrochemical simultaneous movement of an ion down its (actively maintained)electro- PASSIVE Simple Diffusion Transport is driven by and in the in of the electrochemical gradient. Membrane channels are often Transport rate varies linearly with the electrochemical gradient Facilitated Diffusion Transport is in the direction of the electrochemical gradient AND is ediated by a carrier protein. Transport is specific. Transport rate reaches a maximum when all carrier molecules are oCCUpe Carrier-mediated transport: A carrier is a membrane-spanning transport protein that binds one or more species on one side of the membrane and then undergoes a transformational change, releases the species on the other side, and returns to the original state Carriers that transfer a single solute across the membrane are called uni- There are also carriers that transport two or more solute species such that the transfer of one depends on the coupled transfer of the others, either in the same direction(symport) or in the opposite direction (antiport) Primary active transport: Na*-K* ATPase(the sodium pump) and Ca ATPase(the calcium pump)are two examples of primary active transporters The calcium pump is more fully described in Chapter 6, Cardiovascular
Carrier-mediated transport: A carrier is a membrane-spanning transport protein that binds one or more species on one side of the membrane and then undergoes a transformational change, releases the species on the other side, and returns to the original state. • Carriers that transfer a single solute across the membrane are called uniports. • There are also carriers that transport two or more solute species such that the transfer of one depends on the coupled transfer of the others, either in the same direction (symport) or in the opposite direction (antiport). Primary active transport: Na+–K+ ATPase (the sodium pump) and Ca++– ATPase (the calcium pump) are two examples of primary active transporters. The calcium pump is more fully described in Chapter 6, “Cardiovascular Physiology.” 12 PDQ PHYSIOLOGY Table 1–2 Membrane Transport Mechanisms Class Subclasses Features ACTIVE Primary Active Metabolic energy is applied directly and stoichiometrically to accomplish transport AGAINST an electrochemical gradient. Secondary Active Energy for transport derives from simultaneous movement of an ion down its (actively maintained) electrochemical gradient. PASSIVE Simple Diffusion • Transport is driven by and in the direction of the electrochemical gradient. • Membrane channels are often involved. • Transport rate varies linearly with the electrochemical gradient Facilitated Diffusion • Transport is in the direction of the electrochemical gradient AND is mediated by a carrier protein. • Transport is specific. • Transport rate reaches a maximum when all carrier molecules are occupied
Chapter 1 General Physiologic Processes The sodium pump is present, to a varying extent, in nearly all animal cells. Up to 4,000 per um2 are found in the thick ascending limb of the loop of Henle, and as few as sl per um are found in the erythrocytes. Its distri- bution over the plasma membrane can be highly nonuniform. For exam- ple, the epithelial cells, such as renal tubular cells, have all the pumps located on the basolateral side Na*-K+ ATPase translocates, in a reciprocal manner, 3Na* outwardly and K inwardly across the membrane and at the expense of one molecule of ATp. This 3: 2: 1 stoichiometry remains constant over a wide range of mem brane potentials as well as the cytosolic or extracellular concentrations of LATP The rate of Na*-K+ pumping is slow(about 100 cycles. sec-I,trans- porting about 50 pmol. cm-.sec-), compared with the rate of Na* entry dur g an action potential (1,000 pmol. cm-.sec), and is modulated by sev- eral factors. The pumping rate is increased by significant depolarization, insulin, B2-adrenergic agonists and aldosterone. and decreased by significant hyperpolarization, extracellular ouabain, and a-adrenergic agonists Secondary active transport: Unlike ATP-dependent ion pumps, second- arily active carriers do not require stoichiometric hydrolysis of ATP for solute transport, and they show saturation of transport as a function of ion concentration A common feature is that the driving force for these carriers must be reated by primarily active transporters that establish the requisite con- centration gradients Many such carriers rely on the Nat gradient that is built up across cell membranes by Na-K+-ATPase. Typical examples are the Na*-glucose co-transporter(SGLT1), the Na*-H* exchanger that is found in most cells, and the amino acid transporters that are found in the early portions of the proximal convoluted tubule in the kidney. Other carriers are not driven by the gradient for [Na*]. Examples are(1) the K+-CI- co-transporter that removes KCl and water from cells and (2)the band-3 protein(capnophorin) transporter that exchanges Ch- for HCO--across the erythrocyte membrane for the purpose of facili- tating carbon dioxide( CO,)transport away from metabolically active tissues. The phenomenon is often called the chloride shift. Band 3 transports monovalent anions other than Cl-and HCO,"but much slower rate. They include nitrate(NO"), sulfate(HSO.") phosphate(H_.), superoxide anion O2", and hydroxyl ion(oH-)
The sodium pump is present, to a varying extent, in nearly all animal cells. Up to 4,000 per µm2 are found in the thick ascending limb of the loop of Henle, and as few as ≤1 per µm2 are found in the erythrocytes. Its distribution over the plasma membrane can be highly nonuniform. For example, the epithelial cells, such as renal tubular cells, have all the pumps located on the basolateral side. Na+–K+ ATPase translocates, in a reciprocal manner, 3Na+ outwardly and 2K+ inwardly across the membrane and at the expense of one molecule of ATP. This 3:2:1 stoichiometry remains constant over a wide range of membrane potentials as well as the cytosolic or extracellular concentrations of Na+, K+, and ATP. The rate of Na+–K+ pumping is slow (about 100 cycles. sec–1 , transporting about 50 pmol.cm–2 .sec–1 ), compared with the rate of Na+ entry during an action potential (≈1,000 pmol.cm–2 .sec–1 ), and is modulated by several factors. The pumping rate is • increased by significant depolarization, insulin, β2-adrenergic agonists and aldosterone; and • decreased by significant hyperpolarization, extracellular ouabain, and α-adrenergic agonists. Secondary active transport: Unlike ATP-dependent ion pumps, secondarily active carriers do not require stoichiometric hydrolysis of ATP for solute transport, and they show saturation of transport as a function of ion concentration. A common feature is that the driving force for these carriers must be created by primarily active transporters that establish the requisite concentration gradients. • Many such carriers rely on the Na+ gradient that is built up across cell membranes by Na+–K+–ATPase. Typical examples are the Na+–glucose co-transporter (SGLT1), the Na+–H+ exchanger that is found in most cells, and the amino acid transporters that are found in the early portions of the proximal convoluted tubule in the kidney. • Other carriers are not driven by the gradient for [Na+]. Examples are (1) the K+–Cl– co-transporter that removes KCl and water from cells and (2) the band-3 protein (capnophorin) transporter that exchanges Cl– for HCO3 – across the erythrocyte membrane for the purpose of facilitating carbon dioxide (CO2) transport away from metabolically active tissues. The phenomenon is often called the chloride shift. Band 3 transports monovalent anions other than Cl– and HCO3 – but at a much slower rate. They include nitrate (NO3 –), sulfate (HSO4 –), phosphate (H2PO4 –), superoxide anion O2 –, and hydroxyl ion (OH–). Chapter 1 General Physiologic Processes 13
PDQ PHYSIOLOGY Passive transport. Substances are said to be transported passively acr plasma membrane when metabolic energy is not directly applied and when the driving force is one or more of (1)a difference in concentration, (2)a dif- ference in electrical potential, or(3)a difference in osmolarity. Membrane conductance: Only lipid-soluble(also called hydrophobic or nonpolar)compounds, gases, and water cross the plasma membrane with relative ease. Of these, water is believed to cross by specific water channels, whereas the other two cross by permeating the lipid bilayer. As expected, their rates of permeation vary directly with lipid solubility and inversely ith molecular size. All gas transport occurs by simple diffusion down a concentration(partial pressure)gradient. The plasma membrane offers lough resistance to make its permeability to gas diffusion only about 1% of that found in water. Nevertheless, gases move across quickly because th membrane is only 3 to 5 nm thick. The plasma membrane is very poorly conductive for water-soluble mol ecules and almost impermeable to charged molecules, even to such small monovalent ions as Na* and Cl. However, cells have developed techniques for the controlled modification of membrane conductance to na. K+ cat+ and Ch so that these ions can cross the plasma membrane by passive mech anisms under some circumstances. This selective and regulated conductance bestowed by channel proteins, a class of membrane-spanning proteins that form ion channels. Ion channels are assembled so as to have three essen- tial properties: (1)they form a central pore(Figure 1-6)through which ions flow down their electrochemical gradient; (2)they include a selectivity fil- ter that controls which ions are permitted to flow through the pore; and (3 they incorporate a gating structure that switches the channel between the open and closed state. The gating structure may be sensitive to electrical (voltage-gated channels), chemical (ligand-gated channels), or mechani cal forces The basic pore-forming structure of ion channels is called the a-subunit. It is formed, in many cases, by four monomeric assemblies(see Figure 1-6) each consisting of membrane-spanning domains that are linked serially by amino acid chains looping into the cytosol or into the extracellular space. Many voltage-gated channels comprise the pore-forming a-subunit plus other accessory subunits. For example, the voltage-gated Ca**channel in most tissues consists of four subunits(a1, 02, 8, and B). In skeletal muscle, it tains an additional Y-subunit Accessory subunits do not conduct ion flow, but they do modulate the function of the a-subunit with respect to its gating and current kinetics or sensitivity to extracellular and cytosolic factors. lon channels can be in one of three states: closed, open, or inactivated When a channel is in the closed state, no ions flow through it, but the channel can be activated (i.e,"gated"to be in the open"state)
Passive transport. Substances are said to be transported passively across the plasma membrane when metabolic energy is not directly applied and when the driving force is one or more of (1) a difference in concentration, (2) a difference in electrical potential, or (3) a difference in osmolarity. Membrane conductance: Only lipid-soluble (also called hydrophobic or nonpolar) compounds, gases, and water cross the plasma membrane with relative ease. Of these, water is believed to cross by specific water channels, whereas the other two cross by permeating the lipid bilayer. As expected, their rates of permeation vary directly with lipid solubility and inversely with molecular size. All gas transport occurs by simple diffusion down a concentration (partial pressure) gradient. The plasma membrane offers enough resistance to make its permeability to gas diffusion only about 1% of that found in water. Nevertheless, gases move across quickly because the membrane is only 3 to 5 nm thick. The plasma membrane is very poorly conductive for water-soluble molecules and almost impermeable to charged molecules, even to such small monovalent ions as Na+ and Cl–. However, cells have developed techniques for the controlled modification of membrane conductance to Na+, K+, Ca++, and Cl– so that these ions can cross the plasma membrane by passive mechanisms under some circumstances. This selective and regulated conductance is bestowed by channel proteins, a class of membrane-spanning proteins that form ion channels. Ion channels are assembled so as to have three essential properties: (1) they form a central pore (Figure 1–6) through which ions flow down their electrochemical gradient; (2) they include a selectivity filter that controls which ions are permitted to flow through the pore; and (3) they incorporate a gating structure that switches the channel between the open and closed state. The gating structure may be sensitive to electrical (voltage-gated channels), chemical (ligand-gated channels), or mechanical forces. The basic pore-forming structure of ion channels is called the α-subunit. It is formed, in many cases, by four monomeric assemblies (see Figure 1–6), each consisting of membrane-spanning domains that are linked serially by amino acid chains looping into the cytosol or into the extracellular space. Many voltage-gated channels comprise the pore-forming α-subunit plus other accessory subunits. For example, the voltage-gated Ca++ channel in most tissues consists of four subunits (α1, α2, δ, and β). In skeletal muscle, it contains an additional γ-subunit. Accessory subunits do not conduct ion flow, but they do modulate the function of the α-subunit with respect to its gating and current kinetics or sensitivity to extracellular and cytosolic factors. Ion channels can be in one of three states: closed, open, or inactivated. • When a channel is in the closed state, no ions flow through it, but the channel can be activated (i.e., “gated” to be in the “open” state). 14 PDQ PHYSIOLOGY