《医学生理学 Medical Physiology》参考教材资料（PDF电子书籍）Uwe Ackermann. PDQ Physiology, 2002, Uwe Ackerman

Chapter 1 General Physiologic Processes 25 Determination. Eion can be measured directly only when there is but one ion species present. Therefore, Eon is normally calculated from the existing concentrations of the ion species of interest and the valence(z)of the ion: intracellular concentration of the ion extracellular concentration of the Significance. Eion is a fictitious number in that it represents an electrical force that is not likely to be actually present. The electrical force that is present and measurable across the plasma membrane is the membrane The magnitude and polarity of Eion are equal to the electrical potential that would have to be applied to the inside of the cell if the existing con centration difference for that ion is to be maintained by an opposing electrical force alone If Eion for a given ion species is equal to the membrane potential of an electrically resting cell, it is likely that the steady-state distribution of the ion on both sides of the plasma membrane is determined by passive transport mechanisms only If tial of the cell: transport mechanisms are involved taining the distribution of the ion across the plasma membrane. Resting membrane potential. Definition. Erest is the voltage that can be measured across the plasma membrane of the electrically resting cell. It is not simply the algebraic sum of all ion equilibrium potentials because that sum does not account for voltage losses resulting from the flow of each ion through the resistance of the membrane Determination. The resting membrane potential of a cell is usually determined by direct voltage measurement. However, it can be calculated with the help of the Goldman-Hodgkin-Katz equation: Erest=61 log PxK+l+ PNa Nao+Pclchl+. PxK'h +Pna Na+ PcCb+ Where Erest= resting membrane potential Px= membrane permeability coefficient for ion species X K or K= potassium ion Cl or cI-= chloride 0 extracellular concentration i= intracellular concentration

Determination. Eion can be measured directly only when there is but one ion species present. Therefore, Eion is normally calculated from the existing concentrations of the ion species of interest and the valence (z) of the ion: Eion = – 61 log intracellular concentration of the ion z extracellular concentration of the ion Significance. Eion is a fictitious number in that it represents an electrical force that is not likely to be actually present. The electrical force that is present and measurable across the plasma membrane is the membrane potential. • The magnitude and polarity of Eion are equal to the electrical potential that would have to be applied to the inside of the cell if the existing con￾centration difference for that ion is to be maintained by an opposing electrical force alone. • If Eion for a given ion species is equal to the membrane potential of an electrically resting cell, it is likely that the steady-state distribution of the ion on both sides of the plasma membrane is determined by passive transport mechanisms only. • If Eion is different from the resting membrane potential of the cell, active transport mechanisms are involved in maintaining the distribution of the ion across the plasma membrane. Resting membrane potential. Definition. Erest is the voltage that can be measured across the plasma membrane of the electrically resting cell. It is not simply the algebraic sum of all ion equilibrium potentials because that sum does not account for voltage losses resulting from the flow of each ion through the resistance of the membrane. Determination. The resting membrane potential of a cell is usually determined by direct voltage measurement. However, it can be calculated with the help of the Goldman-Hodgkin-Katz equation: Erest = 61 log PK[K+ ]o + PNa[Na+ ]o + PCl[Cl–]i +... PK[K+ ]i + PNa[Na+ ]i + PCl[Cl–]o +... Where Erest = resting membrane potential PX = membrane permeability coefficient for ion species X K or K+ = potassium ion Na or Na+ = sodium ion Cl or Cl– = chloride ion o = extracellular concentration i = intracellular concentration Chapter 1 General Physiologic Processes 25

PDQ PHYSIOLOGY Action potential. Definition. An action potential is a response in which the membrane potential changes transiently from Erest to a peak value that is more positive than Erest (Figure 1-11). It is initiated when a stimulus depolarizes the membrane to a certain voltage threshold Levels of depolarization that fail to reach the threshold also fail to initiate an action potential Transmembrane currents. Action potentials in nerves arise mostly from conductance changes in Nat and K+ channels. Both are activated at mem- brane potentials near-40 to-50 mV. The Na* channels are activated and inactivated rapidly. The K* channels are of the outwardly rectifying type and a more complicated behavi The large inward current creating the upstroke of the action potential in many, but not all, excitable cells is carried by Nat, after a sufficient stimulus has raised the membrane potential from Erest to the gating volt age for iNa. The resulting influx of Na+ depolarizes the cell further and causes more Na* channels to open in a regenerative process that drives 20 岳-60}E E------- TIME ms membrane potential from Erest ng volt- K' efflux causes the subsequent fall in membrane potential. There is a slight hyperpolarization before a variety of small currents restore membrane voltage to emest resting membrane potential; ENa, Ex= ion equilibrium potentials for Na and K', respectively

Action potential. Definition. An action potential is a response in which the membrane potential changes transiently from Erest to a peak value that is more positive than Erest(Figure 1–11). It is initiated when a stimulus depolarizes the membrane to a certain voltage threshold. Levels of depolarization that fail to reach the threshold also fail to initiate an action potential. Transmembrane currents. Action potentials in nerves arise mostly from conductance changes in Na+ and K+ channels. Both are activated at mem￾brane potentials near –40 to –50 mV. The Na+ channels are activated and inactivated rapidly. The K+ channels are of the outwardly rectifying type and have a more complicated behavior. • The large inward current creating the upstroke of the action potential in many, but not all, excitable cells is carried by Na+, after a sufficient stimulus has raised the membrane potential from Erest to the gating volt￾age for iNa. The resulting influx of Na+ depolarizes the cell further and causes more Na+ channels to open in a regenerative process that drives 26 PDQ PHYSIOLOGY ENa EK Erest 60 40 20 0 –20 –40 –60 –80 MEMBRANE POTENTIAL (mV) 0 2 4 TIME (ms) Figure 1–11 Changes in membrane voltage during a typical nerve action potential. A stimu￾lus, applied at 0 ms, causes a gradual rise in membrane potential from Erest to the gating volt￾age for Na+ channels. When the gating voltage is reached, the membrane potential begins to rise sharply toward ENa. K+ efflux causes the subsequent fall in membrane potential. There is a slight hyperpolarization before a variety of small currents restore membrane voltage to Erest. Erest = resting membrane potential; ENa, EK = ion equilibrium potentials for Na+ and K+ , respectively

Chapter 1 General Physiologic Processes the membrane potential toward the sodium equilibrium potential(eNa) After <I ms and before ENa is reached, the inward current diminishes when the channels are inactivated by closure of the h-gate(see Figure 1-6). They cannot be activated again until some time after the cell has repolarized Reactivation of the Na* channels is a much slower process than their activation, and this is responsible for the refractory period of excitable cells because a subsequent action potential can occur only when Na* channels can be opened again. Delayed rectifier-type outwardly rectifying K* channels activate more slowly than do the Na* channels and do not inactivate nearly as quickly. A sufficient number of them are open only by the time most of the fast inactivating Na* channels are already closed and iNa is declining. At that point, K* ions leave the cell rapidly, driven by the K gradient, and con tinue to leave it through the open channels. This produces the down stroke of the action potential. The potassium current stops when the membrane potential reaches the potassium equilibrium potential (about-80 mv). This is slightly more negative than normal Erest, and the difference is called after-hyperpolarization. When all net ion trans port has stopped, the membrane potential settles again at the resting level 4o During the period between action potentials the Na*/K+ pump restores ormal the slight ionic imbalances that are left after the action potential. l Chemical communication Some lipid-soluble chemicals, such as steroid hormones, thyroid hormone, or vitamin D, cross the plasma membrane of their target cells and cause bio- logic responses after binding to receptors that are located in the cytosol or n the nuclear envelope. Many chemicals elicit responses in cells without actually crossing the plasma membrane. This requires interaction of the chemical (the first mes- senger)with a membrane receptor and consequent intracellular activation of a variety of second messenger systems. Some second messengers, such as Ca++ or cyclic guanosine monophosphate (cGMP), couple the signal directly, whereas others operate by way of kinases or calmodulin rThe inside of the cell has a slight excess of Na* and a slight deficit of K*. It should be noted that these imbalances are so small that several hundred thousand action potentials could be generated before the cell would run low on K-

the membrane potential toward the sodium equilibrium potential (ENa). After <1 ms and before ENa is reached, the inward current diminishes when the channels are inactivated by closure of the h-gate (see Figure 1–6). They cannot be activated again until some time after the cell has repolarized. Reactivation of the Na+ channels is a much slower process than their activation, and this is responsible for the refractory period of excitable cells because a subsequent action potential can occur only when Na+ channels can be opened again. • Delayed rectifier-type outwardly rectifying K+ channels activate more slowly than do the Na+ channels and do not inactivate nearly as quickly. A sufficient number of them are open only by the time most of the fast￾inactivating Na+ channels are already closed and iNa is declining. At that point, K+ ions leave the cell rapidly, driven by the K+ gradient, and con￾tinue to leave it through the open channels. This produces the down￾stroke of the action potential. The potassium current stops when the membrane potential reaches the potassium equilibrium potential (about –80 mv). This is slightly more negative than normal Erest, and the difference is called after-hyperpolarization. When all net ion trans￾port has stopped, the membrane potential settles again at the resting level. During the period between action potentials the Na+/K+ pump restores to normal the slight ionic imbalances that are left after the action potential.|| Chemical Communication Some lipid-soluble chemicals, such as steroid hormones, thyroid hormone, or vitamin D, cross the plasma membrane of their target cells and cause bio￾logic responses after binding to receptors that are located in the cytosol or on the nuclear envelope. Many chemicals elicit responses in cells without actually crossing the plasma membrane. This requires interaction of the chemical (the first mes￾senger) with a membrane receptor and consequent intracellular activation of a variety of second messenger systems. Some second messengers, such as Ca++ or cyclic guanosine monophosphate (cGMP), couple the signal directly, whereas others operate by way of kinases or calmodulin. Chapter 1 General Physiologic Processes 27 ||The inside of the cell has a slight excess of Na+ and a slight deficit of K+. It should be noted that these imbalances are so small that several hundred thousand action potentials could be generated before the cell would run low on K+

28 PDQ PHYSIOLOGY Membrane r These are membrane-spanning proteins that bind a specific signaling mol ecule(=ligand)and then initiate cascades that result in a biologic response of the target cell. They are grouped according to their transduction mech- anisms into(1) ion channel-linked,(2) enzyme-linked,(3)tyrosine kinase-linked, or(4)G protein-linked receptors. Whereas any one recep- tor recognizes only one ligand that occurs naturally in the body, many lig- ands are recognized by more than one type of receptor. lon channel-linked receptors. These are receptors that are associated directly with an ion channel. When such a receptor is activated by its ligand, it modulates channel conductance. Enzyme-linked receptors. These receptors are linked to or incorporate an enzyme within the intracellular domain of the membrane-spanning protein. Examples are atrial natriuretic peptide receptors linked to intrinsic (particulate)guanylate cyclase and platelet-derived growth factor receptors ith intrinsic tyrosine kinase domains(Figure 1-12A) Tyrosine phosphatases. Several membrane-spanning tyrosine phos- phatases have been identified, but their physiologic importance remains unclear. Their extracellular domains have sequences that could act as recep tors. Their biologic effects would, presumably, be dephosphorylation of pro- eins that were phosphorylated by tyrosine kinases. Tyrosine kinase-linked receptors. These do not have tyrosine kinase domains in their cytosolic tail. However, they respond to ligand binding in the extracellular domain with formation of a dimerized complex whose intracellular domains bind and activate cytosolic protein-tyrosine kinase The activated kinase then phosphorylates tyrosine residues in the receptor and leads to biologic activity( Figure 1-12B G protein-linked receptors. This large class of membrane receptors is characterized by being coupled with intracellular effector mechanisms through a G protein. Each receptor consists of a single polypeptide chain that threads back and forth across the lipid bilayer and has an extracellular ligand-binding domain and an intracellular domain for G-protein binding G proteins. G proteins are couplers that link membrane receptors occa- ionally to an ion channel but most often to the intracellular enzyme that

Membrane Receptors These are membrane-spanning proteins that bind a specific signaling mol￾ecule (= ligand) and then initiate cascades that result in a biologic response of the target cell. They are grouped according to their transduction mech￾anisms into (1) ion channel–linked, (2) enzyme-linked, (3) tyrosine kinase–linked, or (4) G protein–linked receptors. Whereas any one recep￾tor recognizes only one ligand that occurs naturally in the body, many lig￾ands are recognized by more than one type of receptor. Ion channel–linked receptors. These are receptors that are associated directly with an ion channel. When such a receptor is activated by its ligand, it modulates channel conductance. Enzyme-linked receptors. These receptors are linked to or incorporate an enzyme within the intracellular domain of the membrane-spanning protein. Examples are atrial natriuretic peptide receptors linked to intrinsic (particulate) guanylate cyclase and platelet-derived growth factor receptors with intrinsic tyrosine kinase domains (Figure 1–12A). Tyrosine phosphatases. Several membrane-spanning tyrosine phos￾phatases have been identified, but their physiologic importance remains unclear. Their extracellular domains have sequences that could act as recep￾tors. Their biologic effects would, presumably, be dephosphorylation of pro￾teins that were phosphorylated by tyrosine kinases. Tyrosine kinase–linked receptors. These do not have tyrosine kinase domains in their cytosolic tail. However, they respond to ligand binding in the extracellular domain with formation of a dimerized complex whose intracellular domains bind and activate cytosolic protein-tyrosine kinase. The activated kinase then phosphorylates tyrosine residues in the receptor and leads to biologic activity (Figure 1–12B). G protein–linked receptors. This large class of membrane receptors is characterized by being coupled with intracellular effector mechanisms through a G protein. # Each receptor consists of a single polypeptide chain that threads back and forth across the lipid bilayer and has an extracellular ligand-binding domain and an intracellular domain for G-protein binding. G proteins. G proteins are couplers that link membrane receptors occa￾sionally to an ion channel but most often to the intracellular enzyme that 28 PDQ PHYSIOLOGY # A class of plasma membrane-associated proteins that are capable of binding GDP and GTP

Chapter 1 General Physiologic Processes 口 Ligar 口 Ligand Tyrosine Kinase △ ctivated Tyrosine Kina Figure 1-12 There is a difference between enzyme-linked receptors that incorporate a tyro- kinase domain and tyrosine kinase-linked receptors. A, Some membrane receptors include a tyrosine kinase domain within their cytosolic tail Ligand binding to such receptors activates le kinase, phosphorylates a tyrosine residue within the receptor tail, and can then phosph rylate and activate other cytosolic enzymes. B, Tyrosine kinase-linked receptors form dimers hen extracellular ligand binds to them. The ate cytosolic tyrosine kinase. The activated kinase then phosphorylates tyrosine residues in the receptor and leads to biologic activity by way of phosphorylation cascades nd messenger. They consist of three subunits, a, B, andy In the resting state, a molecule of guanosine diphosphate(GDP)is bound to the a-subunit( Figure 1-13). Binding of a ligand to the g protein-asso- ated receptor causes a conformational change, dissociation of GDP from the a-subunit and binding of guanosine triphosphate(GTP)in its stead. The combined B-and y-subunits then dissociate; in most cases, the a-GTP-subunit performs the next action. This may be modulation of an ion channel or the activation of the catalytic subunit of one of the distal enzymes, adenylate cyclase, phospholipase C, or a phosphodiesterase The dissociated B-/y-subunit can also activate a phospholipase a and

produces a second messenger. They consist of three subunits, α, β, and γ. In the resting state, a molecule of guanosine diphosphate (GDP) is bound to the α-subunit (Figure 1–13). Binding of a ligand to the G protein–asso￾ciated receptor causes a conformational change, dissociation of GDP from the α-subunit and binding of guanosine triphosphate (GTP) in its stead. The combined β- and γ-subunits then dissociate; in most cases, the α-GTP-subunit performs the next action. This may be modulation of an ion channel or the activation of the catalytic subunit of one of the distal enzymes, adenylate cyclase, phospholipase C, or a phosphodiesterase. The dissociated β-/γ-subunit can also activate a phospholipase A and Chapter 1 General Physiologic Processes 29 P cytosol plasma membrane P Ligand Tyrosine Kinase Catalytic Site P A) cytosol plasma membrane P Ligand Tyrosine Kinase inactive B) P P Tyrosine Kinase activated Figure 1–12 There is a difference between enzyme-linked receptors that incorporate a tyro￾sine kinase domain and tyrosine kinase–linked receptors. A, Some membrane receptors include a tyrosine kinase domain within their cytosolic tail. Ligand binding to such receptors activates the kinase, phosphorylates a tyrosine residue within the receptor tail, and can then phospho￾rylate and activate other cytosolic enzymes. B, Tyrosine kinase–linked receptors form dimers when extracellular ligand binds to them. The intracellular domains of the dimer bind and acti￾vate cytosolic tyrosine kinase. The activated kinase then phosphorylates tyrosine residues in the receptor and leads to biologic activity by way of phosphorylation cascades