《医学生理学 Medical Physiology》参考教材资料（PDF电子书籍）USMLE Road Map - Physiology

2. Ligand binding results in conformational change and activation of the re 3. The activated receptor elicits a response in the target cell, either directly or in directly through the production of a secondary signal termed a second mes- a. Target cell responses include alterations in cellular metabolism and alter ations in gene transcription b Second messenger examples include cAMP, DAG(diacylglycerol), and IP c. Hormone binding to a G-protein results in activation of phospholipase C, which catalyzes phosphatidylinositol 4, 5-diphosphate to form IP, and DAG C. Types of Receptor Classes 1. Intracellular receptors located in the cytoplasm or nucleus of the target cell a. Ligand binding alters the receptor's conformation, exposing th DNA-binding domain. b. Receptors bind specific gene promoter elements and activate transcription of specific genes that results in the synthesis of specific proteins. c. An example is an estrogen receptor in uterine smooth muscle cells 2. There are four types of cell surface receptors( Figure 1-2) a. Nicotinic cholinergic receptors are linked to ligand-gated ion channels that are selectively permeable to specific anions or cations(eg, nicotinic AchRs on muscle cells b. Catalytic receptors are transmembrane proteins that have intrinsic enzy- matic(eg, serine or tyrosine kinase) activity. (I) These receptors do not have catalytic activity themselves. D. Other receptors are linked to proteins with enzymatic activ (2) An example is cytokine receptor signaling through cytoplasmic tyrosine kinase(eg, the JAK/TYK-STAT system d g- Pr d receptors have an extracellular ligand-binding domain nd an intracellular domain that binds g-proteins(Figure 1-3) (1) After ligand binding, the receptors interact with (sure s bunits that (2)G-proteins are heterodimeric, consisting of a, B, and y st 3)G-proteins(a-subunits)bound to GTP interact with and activate spe- cific membrane-bound enzymes, resulting in the production of second messengers that elicit responses in target cells (4)An example is an adenylate cyclase system CELL SIGNALING ERROR-INDUCED DISEASE -Cholera toxin alters G-protein so that guanosine triphosphatase(GTPase) is unable to hydrolyze GTP, resulting in increased production of cAMP -Elevated cAMP in intestinal epithelial cells results in massive gut secretion of water and electrolytes, resulting in severe diarrhea and dehydration

Chapter 1: Cell Physiology 9 N 2. Ligand binding results in conformational change and activation of the re￾ceptor. 3. The activated receptor elicits a response in the target cell, either directly or in￾directly through the production of a secondary signal termed a second mes￾senger. a. Target cell responses include alterations in cellular metabolism and alter￾ations in gene transcription. b. Second messenger examples include cAMP, DAG (diacylglycerol), and IP3. c. Hormone binding to a G-protein results in activation of phospholipase C, which catalyzes phosphatidylinositol 4,5-diphosphate to form IP3 and DAG. C. Types of Receptor Classes 1. Intracellular receptors located in the cytoplasm or nucleus of the target cell are bound by lipophilic ligands, which diffuse through the membrane of the target cell. a. Ligand binding alters the receptor’s conformation, exposing the receptor’s DNA-binding domain. b. Receptors bind specific gene promoter elements and activate transcription of specific genes that results in the synthesis of specific proteins. c. An example is an estrogen receptor in uterine smooth muscle cells. 2. There are four types of cell surface receptors (Figure 1–2): a. Nicotinic cholinergic receptors are linked to ligand-gated ion channels that are selectively permeable to specific anions or cations (eg, nicotinic AchRs on muscle cells). b. Catalytic receptors are transmembrane proteins that have intrinsic enzy￾matic (eg, serine or tyrosine kinase) activity. c. Other receptors are linked to proteins with enzymatic activity. (1) These receptors do not have catalytic activity themselves. (2) An example is cytokine receptor signaling through cytoplasmic tyrosine kinase (eg, the JAK/TYK-STAT system). d. G-protein-linked receptors have an extracellular ligand-binding domain and an intracellular domain that binds G-proteins (Figure 1–3). (1) After ligand binding, the receptors interact with G-proteins. (2) G-proteins are heterodimeric, consisting of
, , and  subunits that dissociate. (3) G-proteins (α-subunits) bound to GTP interact with and activate spe￾cific membrane-bound enzymes, resulting in the production of second messengers that elicit responses in target cells. (4) An example is an adenylate cyclase system. CELL SIGNALING ERROR–INDUCED DISEASE • Cholera –Cholera toxin alters G-protein so that guanosine triphosphatase (GTPase) is unable to hydrolyze GTP, resulting in increased production of cAMP. –Elevated cAMP in intestinal epithelial cells results in massive gut secretion of water and electrolytes, resulting in severe diarrhea and dehydration. CLINICAL CORRELATION 5506ch01.qxd_ccII 2/17/03 2:08 PM Page 9

o PP, Cyclic AMP tracellular enzyme Biological effects Figure 1-2. Examples of cell surface receptors Exterior Transmembrane Figure 1-3. All G-protein-coupled receptor proteins span the membrane seven times. The seven clusters of o acids in the plasma membrane represent hy domains are identified as El-E4 Cytoplasmic loops are identified as C|-C4. Amino acid residues in the hird cytoplasmic loop nearest the C terminal interact with G-proteins

Exterior NH3 + COO– E1 E2 E3 E34 C1 C2 C3 C4 Transmembrane α helix Cytosol Figure 1–3. All G-protein-coupled receptor proteins span the membrane seven times. The seven clusters of amino acids in the plasma membrane represent hy￾drophobic portions of the protein’s α helix. Exterior domains are identified as E1–E4. Cytoplasmic loops are identified as C1–C4. Amino acid residues in the third cytoplasmic loop nearest the C terminal interact with G-proteins. Receptor Membrane Hormone ATP Adenylate cyclase Cyclic AMP Intracellular enzyme Biological effects PPi Figure 1–2. Examples of cell surface receptors. 10 5506ch01.qxd_ccII 2/17/03 2:08 PM Page 10

Chapter 1: Cell Physiology 11 Pseudohypoparathyroidism -Patients exhibit symptoms of hypoparathyroidism with normal or slightly elevated parathyroid hor mone levels -Pertussis toxin blocks the activity of G, allowing adenylate cyclase to stay active and increase CAMP. IV, Membrane potential B. Cells have an exces of. eside m the difference in electrical potential(voltage)be- A. The membrane potential tween the inside and ou mbrane surfaces under resting conditions and exhibit a negative membrane potential at rest 1. Because the K concentration inside the cell is higher than the outside concen- ration, K moves out of the cell, leaving excess negative charges on the inside of the cell membrane 2. The Na'/K pump acts as a second factor to generate negative charges on th inner membrane surface by pumping three Na out and only two K'in 3. The K' efflux is primarily responsible for the resting membrane potential C. The equilibrium potential is the membrane potential that exists if the cell mem brane becomes selectively permeable for an ion, causing the distribution of th ion across the membrane to be at equilibrium 1. The Nernst equation describes the relationship between the concentration gradient of an ion and its equilibrium potential. Thus, an equilibrium poten- al is predicted by the Nernst equation where E=equilibrium potential (volts) T= the absolute temperature F=Faradays constant(2.3 x 10" cal/V/mol) Z= the valence of the ion(+1 for Na,+2 for Ca") In= logarithm to the base c Co= the outside concentration of the positively charged ion Ci= the inside concentration of the positively 2. In nerve cells the resting membrane potential ranges from -80 mV to-90 nV, which is near the K' equilibrium potential. Therefore, nerve cell mem- branes are selectively permeable to K 3. The Nernst equation predicts that the equilibrium potential for K' will be for Na will be positive because Nap is greater than n2 quilibrium poten- ive because Ko is less than K;. It also predicts that the 4. Because the membrane is most permeable to K* and Cl, the actual membrane ial of most cells is around -70 mV D. Resting membrane potential is the potential difference across the cell mem-

Chapter 1: Cell Physiology 11 N • Pseudohypoparathyroidism –Pseudohypoparathyroidism results from a defective G-protein and causes decreased cAMP levels. –Patients exhibit symptoms of hypoparathyroidism with normal or slightly elevated parathyroid hor￾mone levels. • Pertussis (Whooping Cough) –Pertussis toxin blocks the activity of G1, allowing adenylate cyclase to stay active and increase cAMP. IV. Membrane Potential A. The membrane potential is the difference in electrical potential (voltage) be￾tween the inside and outside membrane surfaces under resting conditions. B. Cells have an excess of negative charges at the inside surface of the cell membrane and exhibit a negative membrane potential at rest. 1. Because the K+ concentration inside the cell is higher than the outside concen￾tration, K+ moves out of the cell, leaving excess negative charges on the inside of the cell membrane. 2. The Na+ /K+ pump acts as a second factor to generate negative charges on the inner membrane surface by pumping three Na+ out and only two K+ in. 3. The K+ efflux is primarily responsible for the resting membrane potential. C. The equilibrium potential is the membrane potential that exists if the cell mem￾brane becomes selectively permeable for an ion, causing the distribution of the ion across the membrane to be at equilibrium. 1. The Nernst equation describes the relationship between the concentration gradient of an ion and its equilibrium potential. Thus, an equilibrium poten￾tial is predicted by the Nernst equation: where E = equilibrium potential (volts) R = the gas constant T = the absolute temperature F = Faraday’s constant (2.3 × 104 cal/V/mol) Z = the valence of the ion (+1 for Na+ , +2 for Ca2+) In = logarithm to the base c Co = the outside concentration of the positively charged ion Ci = the inside concentration of the positively charged ion 2. In nerve cells the resting membrane potential ranges from −80 mV to −90 mV, which is near the K+ equilibrium potential. Therefore, nerve cell mem￾branes are selectively permeable to K+ . 3. The Nernst equation predicts that the equilibrium potential for K+ will be negative because K0 is less than Ki . It also predicts that the equilibrium poten￾tial for Na+ will be positive because Na0 is greater than Nai . 4. Because the membrane is most permeable to K+ and Cl− , the actual membrane potential of most cells is around −70 mV. D. Resting membrane potential is the potential difference across the cell mem￾brane in millivolts (mV). E = RT FZ In Co Ci 5506ch01.qxd_ccII 2/17/03 2:09 PM Page 11

12 USMLE Road Map: Physiology 1. The resting membrane potential is established by different permeabilities or conductances of permeable ions. a. For example, the resting membrane potential of nerve cells is more perme able to kt than to nat b. Changes in ion conductance alter currents, which change the membrane C. Hyperpolarization is an increase in membrane potential in which the in- side of the cell becomes more negative. d. Depolarization is a decrease in membrane potential in which the inside of the cell becomes more positive 2. An action potential is a rapid, large decrease in membrane potential (ie, de polarization)(F a. Action potentials usually occur because of increases in the conductance of Na’,Ca, and K. ions. b. The threshold is the membrane potential that induces an increase in Na+ conductance to produce an action pote c. Depolarization produces an opening of the Na channel through fast of the activation d slow cle f the d. Closure of the inactivation gates results in closure of the Na' channel d decreased Na* conductan e. Slow opening of the K' channels increases K conductance higher than Na conductance, resulting in repolarization of the membrane potential E. Thus, repolarization is the return of the membra value due to an outward K- movement 3. The refractory period is the period during which the cell is resistant to a sec- action poten 4. During the relative refractory period only some of the inactivated Nachan- nels are reset and k- channe still open. Thus, another action potential can be elicited if the stimulus is large enough Overshoot Depolarization Figure 1-4. Action potentials

12 USMLE Road Map: Physiology N 50 Membrane potential (mV) 0 –50 –100 Overshoot Rest Depolarization Rest Time Threshold Repolarization Figure 1–4. Action potentials. 1. The resting membrane potential is established by different permeabilities or conductances of permeable ions. a. For example, the resting membrane potential of nerve cells is more perme￾able to K+ than to Na+ . b. Changes in ion conductance alter currents, which change the membrane potential. c. Hyperpolarization is an increase in membrane potential in which the in￾side of the cell becomes more negative. d. Depolarization is a decrease in membrane potential in which the inside of the cell becomes more positive. 2. An action potential is a rapid, large decrease in membrane potential (ie, de￾polarization) (Figure 1–4). a. Action potentials usually occur because of increases in the conductance of Na+ , Ca2+, and K+ ions. b. The threshold is the membrane potential that induces an increase in Na+ conductance to produce an action potential. c. Depolarization produces an opening of the Na+ channel through fast opening of the activation gates and slow closing of the inactivation gates. d. Closure of the inactivation gates results in closure of the Na+ channels and decreased Na+ conductance. e. Slow opening of the K+ channels increases K+ conductance higher than Na+ conductance, resulting in repolarization of the membrane potential. f. Thus, repolarization is the return of the membrane potential to its original value due to an outward K+ movement. 3. The refractory period is the period during which the cell is resistant to a sec￾ond action potential. 4. During the relative refractory period only some of the inactivated Na+ chan￾nels are reset and K+ channels are still open. Thus, another action potential can be elicited if the stimulus is large enough. 5506ch01.qxd_ccII 2/17/03 2:09 PM Page 12

Chapter 1: Cell Physiology 13 5. Propagation of the action potential requires a system that regenerates the ac- l along the creased fiber size and and is dependent on the magnitude of b. Myelinated nerves exhibit saltatory conduction in which the action poten- ial skips from node to node where the voltage-gated Na channels congre ion stimulus occurs slowly so that Na channels may inactivate before enough Nachan Thus, even though the membrane potential exceeds the threshold, no action al is produced 7. Organophosphate poisoning occurs by depolarization block of neuromuscu- ar junctions, thereby inhibiting acetylcholine esterase(AchE)from breaking apart acetylcholine molecules V Structure of skeletal Muscle A. Skeletal muscle is organized into progressively smaller anatomical units B. Muscle fibers are surrounded by a plasma membrane more commonly called the sarcolemma C. Muscle fibers are composed of a bundle of fibrous structures called myofibrils, nd each myofibril is a linear arrangement of repeating structures called sarco- meres D. Sarcomeres are the fundamental contractile unit of skeletal muscle and are char terized by their highly ordered appearance under a polarizing light microscope 1. Thick filaments in the a band are composed primarily of the protein myosi a. Each myosin molecule is composed of six monomers: two protein strands entwined in a helical arrangement (termed heavy chains) and four maller, globular proteins(termed myosin light chains) ere are two es- sential light chains and two myosin regulatory light chains b. Each heavy chain is associated with a globular head. The two globular heads of myosin heavy chains can hydrolyze ATP to ADP and inorgan phosphate and also have the intrinsic ability to interact with actin C. The rod-like region (or tail) stabilizes the protein and tends to self- aggregate spontaneously, thereby forming the thick filament d. Treatment with the proteolytic enzyme trypsin splits myosin into two com- ponents, heavy meromyosin and light meromyosin. Another proteolytic enzyme, papain, cleaves heavy meromyosin into a globular protein, SI, and e. The sites sensitive to proteolytic digestion are regions that allow flexing of the molecule, also called hinge regions 2. Thin filaments are composed of three primary proteins: actin, tropomyosin, a. Actin can exist in two states: globular G-actin and filamentous F-actin b. G-actin polymerizes to form F-actin c. Each G-actin monomer contains binding sites for myosin, tropomyosin d. The basic structure of the thin filament consists of two strands of inter- twined F-actin in a double helical

Chapter 1: Cell Physiology 13 N 5. Propagation of the action potential requires a system that regenerates the ac￾tion potential along the axon. a. Conduction velocity is increased by increased fiber size and myelination and is dependent on the magnitude of the depolarizing current. b. Myelinated nerves exhibit saltatory conduction in which the action poten￾tial skips from node to node where the voltage-gated Na+ channels congre￾gate. 6. Depolarization block occurs when a depolarization stimulus occurs slowly so that Na+ channels may inactivate before enough Na+ channel openings occur. Thus, even though the membrane potential exceeds the threshold, no action potential is produced. 7. Organophosphate poisoning occurs by depolarization block of neuromuscu￾lar junctions, thereby inhibiting acetylcholine esterase (AchE) from breaking apart acetylcholine molecules. V. Structure of Skeletal Muscle A. Skeletal muscle is organized into progressively smaller anatomical units. B. Muscle fibers are surrounded by a plasma membrane more commonly called the sarcolemma. C. Muscle fibers are composed of a bundle of fibrous structures called myofibrils, and each myofibril is a linear arrangement of repeating structures called sarco￾meres. D. Sarcomeres are the fundamental contractile unit of skeletal muscle and are char￾acterized by their highly ordered appearance under a polarizing light microscope (Figure 1–5). 1. Thick filaments in the A band are composed primarily of the protein myosin. a. Each myosin molecule is composed of six monomers: two protein strands intertwined in a helical arrangement (termed heavy chains) and four smaller, globular proteins (termed myosin light chains). There are two es￾sential light chains and two myosin regulatory light chains. b. Each heavy chain is associated with a globular head. The two globular heads of myosin heavy chains can hydrolyze ATP to ADP and inorganic phosphate and also have the intrinsic ability to interact with actin. c. The rod-like region (or tail) stabilizes the protein and tends to self￾aggregate spontaneously, thereby forming the thick filament. d. Treatment with the proteolytic enzyme trypsin splits myosin into two com￾ponents, heavy meromyosin and light meromyosin. Another proteolytic enzyme, papain, cleaves heavy meromyosin into a globular protein, S1, and a rod-like protein, S2. e. The sites sensitive to proteolytic digestion are regions that allow flexing of the molecule, also called hinge regions. 2. Thin filaments are composed of three primary proteins: actin, tropomyosin, and troponin. a. Actin can exist in two states: globular G-actin and filamentous F-actin. b. G-actin polymerizes to form F-actin. c. Each G-actin monomer contains binding sites for myosin, tropomyosin, and troponin I. d. The basic structure of the thin filament consists of two strands of inter￾twined F-actin in a double helical arrangement. 5506ch01.qxd_ccII 2/17/03 2:09 PM Page 13