Chapter 1: Cell Physiology 19 Motor neuron Calcit 一e4。。 Secretory etylcholine cleft Sodium Acetylcholin membrane esterase Receptor Cisternae Actin Figure 1-9. Neuromuscular transmission 1. The key enzyme in the biosynthesis of acetylcholine is choline-O-acet transter ed in the neuronal cell body and is transported to the axon terminal 2. The precursors for the synthesis of acetylcholine are pyruvate and choline. Pyruvate is derived from the metabolism of glucose via glycolysis. Choline is actively taken up by the motor neuron 3. Once synthesized, acetylcholine is packaged into secretory vesicles in the motor nerve terminal 4. An action potential that reaches the motor nerve terminal increases the of acetylcholine into the synaptic cleft. Secretion of acetylcholine in fusion of the vesicles with the plasma membrane(exocytosis)and is a requiring event
Chapter 1: Cell Physiology 19 N Myelin Secretory vesicles Synaptic cleft Calcium Sodium Acetylcholine esterase Receptor Reuptake pump Myosin Attachment Troponin Tropomyosin Active site Actin Depolarization Calcium channel Acetylcholine Cisternae Motor neuron Calcium Muscle cell membrane Figure 1–9. Neuromuscular transmission. 1. The key enzyme in the biosynthesis of acetylcholine is choline-O-acetyltransferase, which is synthesized in the neuronal cell body and is transported to the axon terminal. 2. The precursors for the synthesis of acetylcholine are pyruvate and choline. Pyruvate is derived from the metabolism of glucose via glycolysis. Choline is actively taken up by the motor neuron. 3. Once synthesized, acetylcholine is packaged into secretory vesicles in the motor nerve terminal. 4. An action potential that reaches the motor nerve terminal increases the release of acetylcholine into the synaptic cleft. Secretion of acetylcholine involves fusion of the vesicles with the plasma membrane (exocytosis) and is a Ca2+- requiring event. 5506ch01.qxd_ccII 2/17/03 2:09 PM Page 19
20 USMLE Road Map: Physiology 5. Acetylcholine is rapidly removed from the synaptic cleft via hydrolysis into acetate and choline by the enzyme acetylcholinesterase(AchE) 6. Following hydrolysis of acetylcholine, choline is actively taken up by the nerve L. Neuromuscular transmission involves conversion of chemical signals(ie, acetyl- choline)into electrical signals(ie, an action potential), via the nicotinic AchR, a gand-gated ion channel that acts as a transducer( Figure 1-10) 1. The nicotinic AchR is also a Naand K' ion channel. Acetylcholine bin to the receptor opens the central core of the channel and increases the ce tance of Na and K'to move through the channel. 2. The entry of Na'causes depolarization of the membrane, which if of suffi- cient magnitude to reach threshold, produces an action potential that propa- gates over the entire surface of the muscle fiber(see Figure 1-10) fiber via the T-tubule system and subsequent release of Ca*from the SR. b. If the initial depolarization at the motor endplate does not reach threshold, hen excitation-contraction coupling and muscle contraction does not occur 丽E Time(ms) Figure 1-l0. Relationship between the action potential (A) ind the contractile event(B)in skeletal muscle
20 USMLE Road Map: Physiology N A B –90 0 Membrane potential (mV) 5 4 3 2 1 0 0 20 40 Time (ms) 60 80 100 Tension (grams) Latent period Figure 1–10. Relationship between the action potential (A) and the contractile event (B) in skeletal muscle. 5. Acetylcholine is rapidly removed from the synaptic cleft via hydrolysis into acetate and choline by the enzyme acetylcholinesterase (AchE). 6. Following hydrolysis of acetylcholine, choline is actively taken up by the nerve terminal and used for synthesis of new acetylcholine. I. Neuromuscular transmission involves conversion of chemical signals (ie, acetylcholine) into electrical signals (ie, an action potential), via the nicotinic AchR, a ligand-gated ion channel that acts as a transducer (Figure 1–10). 1. The nicotinic AchR is also a Na+ and K+ ion channel. Acetylcholine binding to the receptor opens the central core of the channel and increases the conductance of Na+ and K+ to move through the channel. 2. The entry of Na+ causes depolarization of the membrane, which if of sufficient magnitude to reach threshold, produces an action potential that propagates over the entire surface of the muscle fiber (see Figure 1–10). a. Crossbridge formation between thick and thin filaments depends on spreading of the action potential from the sarcolemma across the muscle fiber via the T-tubule system and subsequent release of Ca2+ from the SR. b. If the initial depolarization at the motor endplate does not reach threshold, then excitation-contraction coupling and muscle contraction does not occur. 5506ch01.qxd_ccII 2/17/03 2:09 PM Page 20
Chapter 1: Cell Physiology 21 3. The resting membrane potential, or endplate potential, of skeletal muscle approximately -70 mV (the interior of a muscle fiber is negative with respect J. Excitation-contraction coupling refers to a series of events beginning with a muscle fiber action potential (the excitation phase of excitation-contraction cou- pling) and culminating with crossbridge formation and muscle fiber shortening (the contraction phase of excitation-contraction coupli 1. A time lag, known as the latent period, occurs between the initiation of the nuscle fiber action potential and the beginning of the actual contractile event. 2. Initiation of contraction starts with an action potential that begins at the notor endplate and travels along the sarcolemma of the muscle fiber 3. The T-tubules, a continuation of the sarcolemma, carry the action potent to the core of the muscle fiber 4. Portions of the T-tubules are close to the terminal cisternae of the SR. form ing a structure called a triad 5. A Ca-ATPase, or calcium pump, actively pumps calcium from the cyto- lasm into the interior of the 6. An action potential reaching a triad serves as the stimulus for the SR to um into the cytoplasm to allow crossbridge formation an ening. 7. Contraction ceases as the calcium is rapidly pumped back into the SR PHARMACOLOGIC AGENTS AND TOXINS AFFECTING THE NEUROMUSCULAR JUNCTION Curare: This term refers to a group of substances originally used by Amazon Indians to kill animals Curare-like compounds bind with high affinity to the AchR, block binding of acetylcholine, and thereby cause skeletal muscle paralysis. In modern medicine, muscle relaxation during abdominal surgery is the primary clinical use of curare or curare-like drugs. Bungarotoxin: This protein was isolated from cobra snake venom. It binds irreversibly to the AchR, blocks binding of acetylcholine, and like curare causes skeletal muscle paralysis Victims of cobra usually die of suffocation. Botulinum toxin: The toxin produced by Clostridium botulinum inhibits release of acetylcholine from the nerve terminal. Death results from respiratory failure. Clinically, botulinum toxin is used to treat focal dystonias, which are neuromuscular disorders characterized by involuntary and repetitive skele- tal muscle contractions. Examples of such disorders include hemifacial spasms and writer's cramp Local treatment with botulinum toxin produces a chemical denervation. results in excessive release of acetylcholine into the synaptic cleft. Neostigmine and physostigmine: These drugs are anticholinesterase agents. Their principle action is to inhibit AchE; the net effect is to increase the concentration of acetylcholine in the synaptic cleft. Clinically, physostigmine is used to treat glaucoma and myasthenia gravis. Organophosphates: This broad group of agents includes insecticides and so-called nerve gases Organophosphates are extremely toxic due to their essentially irreversible inactivation of AchE. Benzodiazepines (eg, diazepam): These agents are central nervous system depressants that do not act directly on the neuromuscular junction. Their muscle-relaxing effect is due to a depressant effect in the reticular formation of the brainstem Dantrolene: This muscle relaxant acts by direct action on excitation-contraction coupling, inhibiting Cat release by the SR
Chapter 1: Cell Physiology 21 N 3. The resting membrane potential, or endplate potential, of skeletal muscle is approximately −70 mV (the interior of a muscle fiber is negative with respect to the exterior). J. Excitation-contraction coupling refers to a series of events beginning with a muscle fiber action potential (the excitation phase of excitation-contraction coupling) and culminating with crossbridge formation and muscle fiber shortening (the contraction phase of excitation-contraction coupling). 1. A time lag, known as the latent period, occurs between the initiation of the muscle fiber action potential and the beginning of the actual contractile event. 2. Initiation of contraction starts with an action potential that begins at the motor endplate and travels along the sarcolemma of the muscle fiber. 3. The T-tubules, a continuation of the sarcolemma, carry the action potential to the core of the muscle fiber. 4. Portions of the T-tubules are close to the terminal cisternae of the SR, forming a structure called a triad. 5. A Ca2+-ATPase, or calcium pump, actively pumps calcium from the cytoplasm into the interior of the SR. 6. An action potential reaching a triad serves as the stimulus for the SR to release calcium into the cytoplasm to allow crossbridge formation and muscle shortening. 7. Contraction ceases as the calcium is rapidly pumped back into the SR. PHARMACOLOGIC AGENTS AND TOXINS AFFECTING THE NEUROMUSCULAR JUNCTION • Curare: This term refers to a group of substances originally used by Amazon Indians to kill animals. Curare-like compounds bind with high affinity to the AchR, block binding of acetylcholine, and thereby cause skeletal muscle paralysis. In modern medicine, muscle relaxation during abdominal surgery is the primary clinical use of curare or curare-like drugs. • -Bungarotoxin: This protein was isolated from cobra snake venom. It binds irreversibly to the AchR, blocks binding of acetylcholine, and like curare causes skeletal muscle paralysis. Victims of cobra bites usually die of suffocation. • Botulinum toxin: The toxin produced by Clostridium botulinum inhibits release of acetylcholine from the nerve terminal. Death results from respiratory failure. Clinically, botulinum toxin is used to treat focal dystonias, which are neuromuscular disorders characterized by involuntary and repetitive skeletal muscle contractions. Examples of such disorders include hemifacial spasms and writer’s cramp. Local treatment with botulinum toxin produces a chemical denervation. • Black widow spider toxin: This toxin causes clumping of acetylcholine-containing vesicles, which results in excessive release of acetylcholine into the synaptic cleft. • Neostigmine and physostigmine: These drugs are anticholinesterase agents. Their principle action is to inhibit AchE; the net effect is to increase the concentration of acetylcholine in the synaptic cleft. Clinically, physostigmine is used to treat glaucoma and myasthenia gravis. • Organophosphates: This broad group of agents includes insecticides and so-called nerve gases. Organophosphates are extremely toxic due to their essentially irreversible inactivation of AchE. • Benzodiazepines (eg, diazepam): These agents are central nervous system depressants that do not act directly on the neuromuscular junction. Their muscle-relaxing effect is due to a depressant effect in the reticular formation of the brainstem. • Dantrolene: This muscle relaxant acts by direct action on excitation-contraction coupling, inhibiting Ca2+ release by the SR. CLINICAL CORRELATION 5506ch01.qxd_ccII 2/17/03 2:09 PM Page 21
22 USMLE Road Map: Physiology MYASTHENIA GRAVIS Myasthenia gravis is a neuromuscular disease characterized by weakness and marked fatigability It is caused by an autoimmune response in which antibodies made against skeletal muscle AchR block binding of acetylcholine to the receptor. Diagnosis of myasthenia gravis is made by the edrophonium test, in which the patient is given edro- phonium, an anticholinesterase; improvement in muscular strength suggests the disease. Treatments for myasthenia gravis patients include the following -AchE inhibitors increase the concentration of acetylcholine in the synaptic cleft. Excessive treatment th achE inhibitors can cause skeletal muscle weakness via desensitization of ni ad to a cholinergic crisis Corticosteroids suppress the immune system and thereby reduce the concentration of circulating nti-AchR antibod -Immunosuppressant drug therapy, such as azathioprine or, less commonly, cyclosporine, is used in patients with severe disease that does not respond well to corticosteroids. -Removal of the thymus gland also suppresses the immune system because the thymus gland plays tion of t cells. one drawback is that su months or even years after the surgery. Plasmapheresis involves removing plasma from the patient and replacing it with a plasma substi- ute. The overall effect of plasmapheresis is to reduce the concentration of circulating anti-AchR anti VIl. Smooth muscle A. Structure of Smooth muscle 1. The cytoplasm of a smooth muscle cell is homogeneous(with no visible stri- ations)when viewed by light microscopy 2. Specialized contacts between individual smooth muscle cells have two func- tions: in communication and as mechanical linkages a. Gap junctions (nexus)are areas of close opposition (-2 nm)between plasma membranes of separate cells. Gap junctions serve as a low-resistance electrical coupling structure b. Attachment plaques are characterized by a 10-to 30-nm gap between plasma membranes of adjacent cells. These structures may serve as anchor to skeletal muscle. Like skeletal oth muscle counterpart ac mulates and releases Ca2 4. Smooth muscle does not have a T-tubule system. However, surface vesicles called caveolae in individual cells are thought to have an analogous role in transmission of action potentials B. Physiology of Smooth Muscle 1. Smooth muscle is typically subdivided into two classes: unitary, or visceral, smooth muscle and multiunit smooth muscle. 2. Both classes of smooth muscle share the following characteristics b. The motor innervation of smooth muscle is exclusively autonomic, either
22 USMLE Road Map: Physiology N MYASTHENIA GRAVIS • Myasthenia gravis is a neuromuscular disease characterized by weakness and marked fatigability of skeletal muscle. • It is caused by an autoimmune response in which antibodies made against skeletal muscle AchR block binding of acetylcholine to the receptor. • Diagnosis of myasthenia gravis is made by the edrophonium test, in which the patient is given edrophonium, an anticholinesterase; improvement in muscular strength suggests the disease. • Treatments for myasthenia gravis patients include the following: –AchE inhibitors increase the concentration of acetylcholine in the synaptic cleft. Excessive treatment with AchE inhibitors can cause skeletal muscle weakness via desensitization of nicotinic AchR and can lead to a cholinergic crisis. –Corticosteroids suppress the immune system and thereby reduce the concentration of circulating anti-AchR antibodies. –Immunosuppressant drug therapy,such as azathioprine or, less commonly, cyclosporine, is used in patients with severe disease that does not respond well to corticosteroids. –Removal of the thymus gland also suppresses the immune system because the thymus gland plays a role in maturation of T cells. One drawback is that sustained improvement may not begin until months or even years after the surgery. –Plasmapheresis involves removing plasma from the patient and replacing it with a plasma substitute. The overall effect of plasmapheresis is to reduce the concentration of circulating anti-AchR antibodies. VII. Smooth Muscle A. Structure of Smooth Muscle 1. The cytoplasm of a smooth muscle cell is homogeneous (with no visible striations) when viewed by light microscopy. 2. Specialized contacts between individual smooth muscle cells have two functions: in communication and as mechanical linkages. a. Gap junctions (nexus) are areas of close opposition (~2 nm) between plasma membranes of separate cells. Gap junctions serve as a low-resistance electrical coupling structure. b. Attachment plaques are characterized by a 10- to 30-nm gap between plasma membranes of adjacent cells. These structures may serve as anchor points for thin filaments. 3. Smooth muscle cells contain SR but in less abundant quantities compared to skeletal muscle. Like skeletal muscle SR, the smooth muscle counterpart accumulates and releases Ca2+. 4. Smooth muscle does not have a T-tubule system. However, surface vesicles called caveolae in individual cells are thought to have an analogous role in transmission of action potentials. B. Physiology of Smooth Muscle 1. Smooth muscle is typically subdivided into two classes: unitary, or visceral, smooth muscle; and multiunit smooth muscle. 2. Both classes of smooth muscle share the following characteristics: a. Smooth muscle is capable of contractions that are slow in onset but are sustained for long periods of time with relatively little energy input required. b. The motor innervation of smooth muscle is exclusively autonomic, either parasympathetic or sympathetic. CLINICAL CORRELATION 5506ch01.qxd_ccII 2/17/03 2:09 PM Page 22
Chapter 1: Cell Physiology 23 c. All smooth muscle exhibits a certain degree of ng tension; contractions are superimposed on this tone. 3. Visceral smooth muscle performs important functions in the vascular system he airways of the lung, the gastrointestinal tract, and the genitourinary tract. The following general characteristics enable visceral smooth muscle to carry out these functions a. Spontaneous activity is initiated in pacemaker areas and spreads through out the entire muscle. Unlike pacemakers in cardiac muscle, smooth mt cle pacemakers move around c. Generally, contractions are initiated by circulating hormones and are not typically initiated by motor nerve impulses. However, contractile activity may be modified and regulated by motor nerve input d. Visceral smooth muscle is widely distributed in a variety of tissues and or gans. Examples include the gastrointestinal tract, uterus, and arterioles. e. Spontaneous activity in visceral smooth muscle results from at least two types of fluctuations in electrical activity: (1)Slow waves of depolarization are produced when the threshold (2 )Spontaneous prepotentials, or spike potentials, produce an asyn chronous discharge resulting in irregular contractions such as occurs in the nonpregna ant uterus f. Unlike skeletal muscle, smooth muscle can contract or relax in response to either neuronal or humoral stimulation g. Calcium is the signal for contraction in smooth musde, binds to calmod- light chain kinase(MLCK i. Ca2-calmodulin-activated MLCK phosphorylates the heavy meromyosin of myosin and thereby consumes ATP. Phosphorylated myosin has a high affinity for actin, and crossbridges form between myosin and actin. j. Relaxation of smooth muscle can occur through the following mecha- (1)Stimulation of Ca*-pumping activity of either the plasma membrane or the Sr reduces the concentration of Cain the vicinity of the con- tractile elements (2 )The activity of myosin light chain phosphatase can be increased. 3) Phosphorylation of MLCK leads to decreased activity of this enzyme. 4. Multiunit smooth muscle is more similar to skeletal muscle than it is to vis a. Multiunit smooth muscle does not contract spontaneou. mooth muscle ceral smooth muscle but is much less abundant than visceral b. Multiunit smooth muscle is usually activated by motor nerve stimulation. Multiunit smooth muscle is only minimally responsive to circulating hor mones c. Multiunit smooth muscle does not respond to stretch by developing ten d. Examples of multiunit smooth muscle include ciliary muscle(the muscle that focuses the eye), pilomotor(the muscles that cause hair erection and nictitating membranes(in the eyes of cats)
Chapter 1: Cell Physiology 23 N c. All smooth muscle exhibits a certain degree of intrinsic tone, or basal resting tension; contractions are superimposed on this tone. 3. Visceral smooth muscle performs important functions in the vascular system, the airways of the lung, the gastrointestinal tract, and the genitourinary tract. The following general characteristics enable visceral smooth muscle to carry out these functions: a. Spontaneous activity is initiated in pacemaker areas and spreads throughout the entire muscle. Unlike pacemakers in cardiac muscle, smooth muscle pacemakers move around. b. Tension develops in response to stretch. c. Generally, contractions are initiated by circulating hormones and are not typically initiated by motor nerve impulses. However, contractile activity may be modified and regulated by motor nerve input. d. Visceral smooth muscle is widely distributed in a variety of tissues and organs. Examples include the gastrointestinal tract, uterus, and arterioles. e. Spontaneous activity in visceral smooth muscle results from at least two types of fluctuations in electrical activity: (1) Slow waves of depolarization are produced when the threshold is reached, as occurs in longitudinal muscles of the intestines. (2) Spontaneous prepotentials, or spike potentials, produce an asynchronous discharge resulting in irregular contractions such as occurs in the nonpregnant uterus. f. Unlike skeletal muscle, smooth muscle can contract or relax in response to either neuronal or humoral stimulation. g. Calcium is the signal for contraction in smooth muscle. h. Because smooth muscle does not contain troponin, Ca2+ binds to calmodulin and then the Ca2+-calmodulin complex activates the enzyme myosin light chain kinase (MLCK). i. Ca2+-calmodulin-activated MLCK phosphorylates the heavy meromyosin component of myosin and thereby consumes ATP. Phosphorylated myosin has a high affinity for actin, and crossbridges form between myosin and actin. j. Relaxation of smooth muscle can occur through the following mechanism: (1) Stimulation of Ca2+-pumping activity of either the plasma membrane or the SR reduces the concentration of Ca2+ in the vicinity of the contractile elements. (2) The activity of myosin light chain phosphatase can be increased. (3) Phosphorylation of MLCK leads to decreased activity of this enzyme. 4. Multiunit smooth muscle is more similar to skeletal muscle than it is to visceral smooth muscle but is much less abundant than visceral smooth muscle. a. Multiunit smooth muscle does not contract spontaneously. b. Multiunit smooth muscle is usually activated by motor nerve stimulation. Multiunit smooth muscle is only minimally responsive to circulating hormones. c. Multiunit smooth muscle does not respond to stretch by developing tension. d. Examples of multiunit smooth muscle include ciliary muscle (the muscle that focuses the eye), pilomotors (the muscles that cause hair erection), and nictitating membranes (in the eyes of cats). 5506ch01.qxd_ccII 2/17/03 2:09 PM Page 23