Chapter 7 Excitation of Skeletal Muscle PDF

CHAPTER 7...

CHAPTER 7 UNIT II Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling (nissle bodies of the neuron Sin RER NEUROMUSCULAR JUNCTION AND in the cytoplasm of the terminal but is absorbed rap- TRANSMISSION OF IMPULSES FROM idly into many small synaptic vesicles, about 300,000 of NERVE ENDINGS TO SKELETAL MUSCLE which are normally in the terminals of a single end plate. FIBERS In the synaptic space are large quantities of the enzyme Skeletal muscle fibers are innervated by large myelinated acetylcholinesterase, which destroys acetylcholine a few * space nerve fibers that originate from large motoneurons in the milliseconds after it has been released from the synaptic blu nerve anterior horns of the spinal cord. As discussed in Chap- vesicles.! & muscle ter 6, each nerve fiber, after entering the muscle belly, ↓ normally branches and stimulates from three to several (neuco musculaa SECRETION OF ACETYLCHOLINE BY THE S hundred skeletal muscle fibers. Each nerve ending makes NERVE TERMINALS a junction, called the neuromuscular junction, with the muscle fiber near its midpoint. The action potential initi- When a nerve impulse reaches the neuromuscular junc- ated in the muscle fiber by the nerve signal travels in both tion, about 125 vesicles of acetylcholine are released from directions toward the muscle fiber ends. With the excep- the terminals into the synaptic space. Some of the details tion of about 2% of the muscle fibers, there is only one of this mechanism can be seen in Figure 7-2, which such junction per muscle fiber. shows an expanded view of a synaptic space with the neu- ral membrane above and the muscle membrane and its subneural clefts below. PHYSIOLOGIC ANATOMY OF THE On the inside surface of the neural membrane are lin- NEUROMUSCULAR JUNCTION—THE ear dense bars, shown in cross section in Figure- 7-2. To MOTOR END PLATE > voltage each side of each dense bar are protein particles that pen- Figure 7-1A and B shows the neuromuscular junction gated etrate the neural membrane; these are voltage-gated cal- channels from a large myelinated nerve fiber to a skeletal muscle cium channels. When an action potential spreads over the fiber. The nerve fiber forms a complex of branching nerve terminal, these channels open and allow calcium ions to comes from the > - terminals that invaginate into the surface of the muscle diffuse from the synaptic space to the interior of the nerve extracellular flaid fiber but lie outside the muscle fiber plasma membrane. terminal. The calcium ions, in turn, are believed to acti- that surrounds terminal axcon the The entire structure is called the motor end plate. It is cov- vate Ca2+-calmodulin–dependent protein kinase, which, ered by one or more Schwann cells that insulate it from in turn, phosphorylates synapsin proteins that anchor the surrounding fluids. j C junctional folds of Me > synaptic Sarcolemma gutter Subneural clefts es increase surface area Figure 7-1. Different views of the motor end plate. A, Longitudinal section through the end plate. B, Surface view of the end plate. C, Electron micrographic appearance of the contact point between a single axon terminal and the muscle fiber membrane. Release Neural Vesicles the subneural clefts lying immediately below the dense sites membrane bar areas, where the acetylcholine is emptied into the syn- aptic space. The voltage-gated sodium channels also line Fetal Ach receptor: the subneural clefts. Dense bar alpha Each acetylcholine receptor is a protein complex that alpha Calcium channels has a total molecular weight of approximately 275,000. s beta The fetal acetylcholine receptor complex is composed of gamma Basal lamina and five subunit proteins, two alpha proteins and one each of acetylcholinesterase beta, delta, and gamma proteins. In the adult, an epsilon ↳ Adult Ach receptor protein substitutes for the gamma protein in this recep- : Acetylcholine alpha tor complex. These protein molecules penetrate all the a receptors way through the membrane, lying side by side in a circle to form a tubular channel, illustrated in Figure 7-3. The Subneural cleft channel remains constricted, as shown in part A of the Voltage-activated Na+ channels figure, until two acetylcholine molecules attach respec- tively to the two alpha subunit proteins. This attachment causes a conformational change that opens the channel, Muscle as shown in part B of the figure. membrane The acetylcholine-gated channel has a diameter of Figure 7-2. Release of acetylcholine from synaptic vesicles at the about 0.65 nanometer, which is large enough to allow the neural membrane of the neuromuscular junction. Note the proximity of the release sites in the neural membrane to the acetylcholine recep- important positive ions—sodium (Na+), potassium (K+), tors in the muscle membrane at the mouths of the subneural clefts. and calcium (Ca2+)—to move easily through the opening. Patch clamp studies have shown that one of these chan- Acetylcholine Opens Ion Channels on Postsynaptic nels, when opened by acetylcholine, can transmit 15,000 Membranes. Figure 7-2 also shows many small acetyl- to 30,000 sodium ions in 1 millisecond. Conversely, nega- choline receptors and voltage-gated sodium channels in tive ions, such as chloride ions, do not pass through the muscle fiber membrane. The acetylcholine-gated ion because of strong negative charges in the mouth of the channels are located almost entirely near the mouths of channel that repel these negative ions. 94  Chapter 7 Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling repels - ve ions like (11) Ach binding & Ach binding +60 site site +40 – – – – +20 – – 0 Millivolts –20 Threshold –40 UNIT II –60 –80 A B C –100 0 15 30 45 60 75 Milliseconds Figure 7-4. End plate potentials (in millivolts). A, Weakened end plate potential recorded in a curarized muscle that is too weak to elicit an action potential. B, Normal end plate potential eliciting a A muscle action potential. C, Weakened end plate potential caused by Na+ botulinum toxin that decreases end plate release of acetylcholine, again too weak to elicit a muscle action potential. Ach Ach – – spreads along the muscle membrane and causes muscle – – contraction.! Ach detach from chemically gated channels Break to – – eof the Released Acetylcholine by Ace- *Destruction tylcholinesterase. The acetylcholine, once released into the synaptic space, continues to activate acetylcholine re- ceptors as long as the acetylcholine persists in the space. However, it is rapidly destroyed by the enzyme acetylcho- linesterase, which is attached mainly to the spongy layer of fine connective tissue that fills the synaptic space be- Breaks ACH V into : tween the presynaptic nerve terminal and the postsynap- choline tic muscle membrane. A small amount of acetylcholine B Aceti a I diffuses out of the synaptic space and is then no longer available to act on the muscle fiber membrane. Figure 7-3. Acetylcholine-gated channel. A, Closed state. B, After The short time that the acetylcholine remains in the acetylcholine (Ach) has become attached and a conformational change has opened the channel, allowing sodium ions to enter the muscle synaptic space—a few milliseconds at most—normally fiber and excite contraction. Note the negative charges at the channel is sufficient to excite the muscle fiber. Then the rapid mouth that prevent passage of negative ions such as chloride ions. removal of the acetylcholine prevents continued muscle re-excitation after the muscle fiber has recovered from its In practice, far more sodium ions flow through the initial action potential.! generated by entry of Nat acetylcholine-gated channels than any other ions for resulting > - in Ap the muscle - exit (by theChemicalennels) " & k two reasons. First, there are only two positive ions S End Plate Potential and Excitation of the Skeletal present in large concentrations—sodium ions in the happens Muscle Fiber. The sudden insurgence of sodium ions extracellular fluid and potassium ions in the intracel- in The into the muscle fiber when the acetylcholine-gated chan- the lular fluid. Second, the negative potential on the inside potibrtic nels open causes the electrical potential inside the fiber at · membrane) of the muscle membrane, −80 to −90 millivolts, pulls the local area of the end plate to increase in the positive the positively charged sodium ions to the inside of the direction as much as 50 to 75 millivolts, creating a local moreNateta - fiber while simultaneously preventing efflux of the pos- potential called the end plate potential. Recall from Chap- itively charged potassium ions when they attempt to ter 5 that a sudden increase in nerve membrane potential pass outward. of more than 20 to 30 millivolts is normally sufficient to As shown in Figure 7-3B, the principal effect of open- initiate more and more sodium channel opening, thus ini- ing the acetylcholine-gated channels is to allow sodium tiating an action potential at the muscle fiber membrane. ions to flow to the inside of the fiber, carrying positive Figure 7-4 illustrates an end plate potential initiat- charges with them. This action creates a local positive ing the action potential. This figure shows three separate potential change inside the muscle fiber membrane, called end plate potentials. End plate potentials A and C are the end plate potential. This end plate potential normally too weak to elicit an action potential, but they do pro- causes sufficient depolarization to open neighboring duce weak local end plate voltage changes, as recorded voltage-gated sodium channels, allowing even greater in the figure. By contrast, end plate potential B is much sodium ion inflow and initiating an action potential that stronger and causes enough sodium channels to open 95  UNIT II Membrane Physiology, Nerve, and Muscle -Choline so that the self-regenerative effect of more and more is actively reabsorbed into the neural terminal to be re- sodium ions flowing to the interior of the fiber initiates an used to form new acetylcholine. This sequence of events action potential. The weakness of the end plate potential occurs within a period of 5 to 10 milliseconds. at point A was caused by poisoning of the muscle fiber 4. The number of vesicles available in the nerve ending is sufficient to allow transmission of only a few thousand S with curare, a drug that blocks the gating action of ace- nerve to muscle impulses. Therefore, for continued tylcholine on the acetylcholine channels by competing for (ACh antagonist function of the neuromuscular junction, new vesicles * drug that a the acetylcholine receptor sites. The weakness of the end need to be re-formed rapidly. Within a few seconds after competes plate potential at point C resulted from the effect of botu- with each action potential is over, coated pits appear in the Ach for its receptors ↳ causing blockage linum toxin, a bacterial poison that decreases the quantity of acetylcholine release by the nerve terminals.! * poison of the channels that & terminal nerve membrane, caused by contractile pro- teins in the nerve ending, especially the protein clathrin, ↳ Sonoenougha stops exocytosis of Ach which is attached to the membrane in the areas of the ↳ resulting end in weak plate potential Safety Factor for Transmission at the Neuromuscu- original vesicles. Within about 20 seconds, the proteins lar Junction—Fatigue of the Junction. Ordinarily, contract and cause the pits to break away to the interior each impulse that arrives at the neuromuscular junction of the membrane, thus forming new vesicles. Within causes about three times as much end plate potential as another few seconds, acetylcholine is transported to the interior of these vesicles, and they are then ready for a that required to stimulate the muscle fiber. Therefore, new cycle of acetylcholine release.! the normal neuromuscular junction is said to have a high safety factor. However, stimulation of the nerve fiber at Drugs That Enhance or Block Transmission at the rates greater than 100 times per second for several min- Neuromuscular Junction same effect ACH utes may diminish the number of acetylcholine vesicles so as much that impulses fail to pass into the muscle fiber. This Drugs That Stimulate the Muscle Fiber by Acetylcholine- en Il Like Action. Several compounds, including methacholine, situation is called fatigue of the neuromuscular junction, carbachol, and nicotine, have nearly the same effect on the these drugs cause and it is the same effect that causes fatigue of synapses in muscle fiber as acetylcholine. The main differences be- muscle spasm the central nervous system when the synapses are overex- tween these drugs and acetylcholine are that the drugs are cited. Under normal functioning conditions, measurable not destroyed by cholinesterase or are destroyed so slowly fatigue of the neuromuscular junction occurs rarely and, that their action often persists for many minutes to several when the fiber hours. The drugs work by causing localized areas of depo- * muscle even then, only at the most exhausting levels of muscle tries to recover from activity.! larization of the muscle fiber membrane at the motor end a contraction , plate where the acetylcholine receptors are located. Then, > the depolarized areas muscle fiber every time the muscle fiber recovers from a previous con- in the * Acetylcholine Formation and Release traction, these depolarized areas, by virtue of leaking ions, start leaking ions Acetylcholine formation and release at the neuromuscular S initiate a new action potential, thereby causing a state of leakage triggers a this Action potential junction occur in the following stages: new muscle spasm.! muscle > - remainscontracted without relaxing 1. Small vesicles, about 40 nanometers in size, are formed > causing contraction again Drugs That Stimulate the Neuromuscular Junction and again by the Golgi apparatus in the cell body of the motoneu- by Inactivating Acetylcholinesterase. Three particularly ~ ron in the spinal cord. These vesicles are then trans- well-known drugs—neostigmine, physostigmine, and diiso- preventingthemustea ported by axoplasm that streams through the core of propyl fluorophosphate—inactivate acetylcholinesterase in S resulting continuous the axon from the central cell body in the spinal cord all in the synapses so that it no longer hydrolyzes acetylcholine. Spasm (contractiona the way to the neuromuscular junction at the tips of the Therefore, with each successive nerve impulse, additional relaxation) peripheral nerve fibers. About 300,000 of these small acetylcholine accumulates and stimulates the muscle fiber vesicles collect in the nerve terminals of a single skeletal repetitively. This activity causes muscle spasm when even muscle end plate. -in RER a few nerve impulses reach the muscle. Unfortunately, it * Anti-Ach esterase drugs : 2. Acetylcholine is synthesized in the cytosol of the nerve can also cause death as a result of laryngeal spasm, which fiber terminal but is immediately transported through smothers a person. - neostigmine inhibitsee the membranes of the vesicles to their interior, where Neostigmine and physostigmine combine with acetyl- it is stored in highly concentrated form—about 10,000 cholinesterase to inactivate the acetylcholinesterase for up - diisopropyl fluorophosphate molecules of acetylcholine in each vesicle. to several hours, after which these drugs are displaced from innitbits Ach-esterase for WEEKS 3. When an action potential arrives at the nerve terminal, the acetylcholinesterase so that the esterase once again be- it opens many calcium channels in the membrane of the comes active. Conversely, diisopropyl fluorophosphate, nerve terminal because this terminal has an abundance which is a powerful nerve gas poison, inactivates acetylcho- of voltage-gated calcium channels. As a result, the cal- linesterase for weeks, which makes this poison particularly cium ion concentration inside the terminal membrane lethal.! increases about 100-fold, which in turn increases the Drugs That Block Transmission at the Neuromuscular rate of fusion of the acetylcholine vesicles with the ter- Junction. A group of drugs known as curariform drugs can minal membrane about 10,000-fold. This fusion makes prevent the passage of impulses from the nerve ending into many of the vesicles rupture, allowing exocytosis of ace- the muscle. For example. %-tubocurarine blocks the action tylcholine into the synaptic space. About 125 vesicles of acetylcholine on the muscle fiber acetylcholine receptors, usually rupture with each action potential. Then, after a thus preventing sufficient increase in permeability of the few milliseconds, the acetylcholine is split by acetylcho- muscle membrane channels to initiate an action potential.! linesterase into acetate ion and choline, and the choline 96  & immestSomat in which * autoimmune disease Chapter 7 Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling : -ting chemical energy into Mechanical energy & Myasthenia Gravis Causes Muscle Weakness characterized by : EXCITATION-CONTRACTION COUPLING Myasthenia gravis, which occurs in about 1 in every 20,000 drooping up a persons, causes muscle weakness because of the inability - of the neuromuscular junctions to transmit enough signals *Transverse Tubule–Sarcoplasmic - difficulty swallowing from the nerve fibers to the muscle fibers. Antibodies that Reticulum System & talking attack the acetylcholine receptors have been demonstrat- Figure 7-5 shows myofibrils surrounded by the T tubule– UNIT II ed in the blood of most patients with myasthenia gravis. sarcoplasmic reticulum system. The T tubules are small Therefore, myasthenia gravis is believed to be an autoim- and run transverse to the myofibrils. They begin at the mune disease in which the patients have developed anti- cell membrane and penetrate all the way from one side bodies that block or destroy their own acetylcholine recep- Sarcolemma < of the muscle fiber to the opposite side. Not shown in the tors at the postsynaptic neuromuscular junction. Regardless of the cause, the end plate potentials that figure is that these tubules branch among themselves and occur in the muscle fibers are mostly too weak to initiate form entire planes of T tubules interlacing among all the opening of the voltage-gated sodium channels, and muscle separate myofibrils. Also, where the T tubules originate fiber depolarization does not occur. If the disease is intense from the cell membrane, they are open to the exterior of enough, the patient may die of respiratory failure as a result the muscle fiber. Therefore, they communicate with the of severe weakness of the respiratory muscles. The disease extracellular fluid surrounding the muscle fiber and con- can usually be ameliorated for several hours by adminis- tain extracellular fluid in their lumens. In other words, the tering neostigmine or some other anticholinesterase drug, T tubules are actually internal extensions of the cell mem- which allows larger than normal amounts of acetylcholine 2 brane. Therefore, when an action potential spreads over a drugs to accumulate in the synaptic space. Within minutes, some that destroy muscle fiber membrane, a potential change also spreads of those affected can begin to function almost normally un- along the T tubules to the deep interior of the muscle til a new dose of neostigmine is required a few hours later.! Attestersa fiber. The electrical currents surrounding these T tubules inhigheriona then elicit the muscle contraction. soitCI the Figure 7-5 also shows a sarcoplasmic reticulum, in MUSCLE ACTION POTENTIAL receptors yellow. This sarcoplasmic reticulum is composed of two causing Ap transmission Almost everything discussed in Chapter 5 regarding the major parts: (1) large chambers called terminal cisternae initiation and conduction of action potentials in nerve usinga that abut the T tubules; and (2) long longitudinal tubules tion fibers applies equally to skeletal muscle fibers, except for that surround all surfaces of the contracting myofibrils.! quantitative differences. Some of the quantitative aspects * Release of Calcium Ions by the of muscle potentials are as follows: more ve - 1. The resting membrane potential is about −80 to −90 Sarcoplasmic Reticulum RMP millivolts in skeletal fibers, about 10 to 20 millivolts One of the special features of the sarcoplasmic reticulum more negative than in neurons. is that within its vesicular tubules is an excess of calcium Slower2. The duration of the action potential is 1 to 5 mil- ions in high concentration. Many of these ions are released & takes longer liseconds in skeletal muscle, about five times as long from each vesicle when an action potential occurs in the time to finish as in large myelinated nerves. adjacent T tubule. neuron 3. & The velocity of conduction is 3 to 5 m/sec, about Figures 7-6 and 7-7 show that the action potential of velocity conduction 1/13 the velocity of conduction in the large myeli- the T tubule causes current flow into the sarcoplasmic is faster than nated nerve fibers that excite skeletal muscle. reticular cisternae where they abut the T tubule. As the muscle action potential reaches the T tubule, the voltage change voltage gated * Action Potentials Spread to the Interior is sensed by dihydropyridine receptors linked to calcium cat the channels of the Muscle Fiber by Way of Transverse release channels, also called ryanodine receptor channels, -in terminal Tubules in the adjacent sarcoplasmic reticular cisternae (see Fig- cistern The skeletal muscle fiber is so large that action poten- ure 7-6). Activation of dihydropyridine receptors triggers tials spreading along its surface membrane cause the opening of the calcium release channels in the cister- almost no current flow deep within the fiber. Maximum nae, as well as in their attached longitudinal tubules. These muscle contraction, however, requires the current to channels remain open for a few milliseconds, releasing penetrate deeply into the muscle fiber to the vicinity calcium ions into the sarcoplasm surrounding the myo- of the separate myofibrils. This penetration is achieved fibrils and causing contraction, as discussed in Chapter 6. by transmission of action potentials along transverse tubules (T tubules) that penetrate all the way through * Calcium Pump Removes Calcium Ions from the the muscle fiber, from one side of the fiber to the other, Myofibrillar Fluid After Contraction Occurs. Once the as illustrated in Figure 7-5. The T tubule action poten- calcium ions have been released from the sarcoplasmic tials cause release of calcium ions inside the muscle tubules and have diffused among the myofibrils, muscle fiber in the immediate vicinity of the myofibrils, and contraction continues as long as the calcium ion concen- these calcium ions then cause contraction. The overall tration remains high. However, a continually active calcium * sequence process is called excitation- contraction coupling.! ofevents by which I & pump located in the walls of the sarcoplasmic reticulum to So cat needs to go back Ap extends from : the SER of the muscle cell 97 1-initiation of A.P in the Sarcolemma (in muscle , not axon terminal of cat reticulum cistern 2- until release in the sarcoplasmic  UNIT II Membrane Physiology, Nerve, and Muscle Myofibrils Sarcolemma trinds Terminal Z disk be cisternae Triad of the reticulum Transverse T-tubules : tubule conducting AP from sarcolemma to deep inside the cell Mitochondrion H zone M line A band Sarcoplasmic S & reticulum (cat released in the Sarcoplason from terminal cistern) Transverse tubule I band Z disk Sarcotubules Figure 7-5. Transverse (T) tubule–sarcoplasmic reticulum system. Note that the T tubules communicate with the outside of the cell membrane and, deep in the muscle fiber, each T tubule lies adjacent to the ends of longitudinal sarcoplasmic reticulum tubules that surround all sides of the actual myofibrils that contract. This illustration was drawn from frog muscle, which has one T tubule per sarcomere, located at the Z disk. A similar arrangement is found in mammalian heart muscle, but mammalian skeletal muscle has two T tubules per sarcomere, located at the A-I band junctions. pumps calcium ions away from the myofibrils back into ions again. The total duration of this calcium pulse in the the sarcoplasmic tubules (see Figure 7-6). This pump, usual skeletal muscle fiber lasts about 1/20 of a second, & pump called SERCA (sarcoplasmic reticulum Ca2+-ATPase), although it may last several times as long in some fibers that returns can concentrate the calcium ions about 10,000-fold inside and several times less in others. In heart muscle, the cal- calcium the tubules. In addition, inside the reticulum is a calcium- cium pulse lasts about one-third of a second because of from Cytoplasm to sarcoplasmic binding protein called calsequestrin, which can bind up to the long duration of the cardiac action potential. reticulum 40 calcium ions for each molecule of calsequestrin.! During this calcium pulse, muscle contraction occurs. Cits home ( after initiating If the contraction is to continue without interruption for the muscle contraction Excitatory Pulse of Calcium Ions. The normal resting long intervals, a series of calcium pulses must be initiated state concentration ( - & S laxed state of the muscle. In susceptible individuals, malignant hyperthermia and Conversely, full excitation of the T tubule and sar- a hypermetabolic crisis may be triggered by exposure to coplasmic reticulum system causes enough release of certain types of anesthetics, including halothane and iso- calcium ions to increase the concentration in the myo- flurane, or succinylcholine. At least six genetic mutations, fibrillar fluid to as high as 2 × 10−4 molar concentration, especially of the ryanodine receptor or dihydropyridine a 500-fold increase, which is about 10 times the level receptor genes, have been shown to increase susceptibil- A mutation of receptors > - increasing the risk required to cause maximum muscle contraction. Imme- ity greatly to developing malignant hyperthermia during of developing malignant diately thereafter, the calcium pump depletes the calcium anesthesia. Little is known about the specific mechanisms hyperthermia mutation in receptors responsible 98 a of cat release regulatio error during for cat influx receptors ? Cant control cat ? -> excess DNA replication ↳ destroyed CDHP & RYR) > - causes excess or uncontrolled contraction- > Causing muscle rigidity  Chapter 7 Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling Nerve terminal Action potential UNIT II + Ca2+ Release Channel (RyR) + (open) DHP + I receptor Ca2+ Sarcoplasmic reticulum found in T-tubules d + Causes opening of + Terminal Cisterne RYR cat to pump ions + Ca2+ Repolarization + + Calsequestrin + + + & during repolarization DHP Closes RyR to Stop + returns cat back pumping cat + Ca2+ SERCA > - to the SR + Ca2+ Release Channel (RyR) - found in reticulum (closed) Cistern in sarcoplasmic cisternal > (in terminal Figure 7-6. Excitation-contraction coupling in skeletal muscle. The top panel shows an action potential in the transverse tubule that causes a conformational change in the voltage-sensing dihydropyridine (DHP) receptors, opening the ryanodine (RyR) Ca2+ release channels in the ter- minal cisternae of the sarcoplasmic reticulum and permitting Ca2+ to diffuse rapidly into the sarcoplasm and initiate muscle contraction. During repolarization (bottom panel), the conformational change in the DHP receptor closes the Ca2+ release channels, and Ca2+ is transported from the sarcoplasm into the sarcoplasmic reticulum by an adenosine triphosphate–dependent calcium pump, called SERCA (sarcoplasmic reticulum Ca2+-ATPase). * function : 1- Accumulation. secretion 2 Process of removing Action potential 3-resequestration > - cations from cytoplasm back to SR (done by SERCA) Sarcolemma Calcium pump Ca Ca ATP required Ca2+ Ca2+ Actin filaments Myosin filaments Figure 7-7. Excitation-contraction coupling in the muscle, showing (1) an action potential that causes release of calcium ions from the sarco- plasmic reticulum and then (2) re-uptake of the calcium ions by a calcium pump. ATP, Adenosine triphosphate. 99  UNIT II Membrane Physiology, Nerve, and Muscle ·> whereby anesthetics interact with these abnormal recep- Cheng H, Lederer WJ: Calcium sparks. Physiol Rev 88:1491, 2008. tors to trigger malignant hyperthermia. It is known, how- Dalakas MC. Immunotherapy in myasthenia gravis in the era of bio- ever, that these mutations cause unregulated passage of cal- logics. Nat Rev Neurol 15:113-124, 2019. cium from the sarcoplasmic reticulum into the intracellular Gilhus NE. Myasthenia gravis. N Engl J Med 37:2570-2581, 2016. Jungbluth H, Treves S, Zorzato F, Sarkozy A, Ochala J, Sewry C, et al. spaces, which in turn causes the muscle fibers to contract Congenital myopathies: disorders of excitation-contraction cou- excessively. These sustained muscled contractions greatly pling and muscle contraction. Nat Rev Neurol 14:151-167, 2018 increase metabolic rate, generating large amounts of heat Meissner G. The structural basis of ryanodine receptor ion channel and causing cellular acidosis, as a well as depletion of en- function. J Gen Physiol 149:1065-1089, 2017. ergy stores. Periasamy M, Maurya SK, Sahoo SK, Singh S, Sahoo SK, Reis FCG, Stachycardia Symptoms of malignant include muscle rigidity, high et al. Role of SERCA pump in muscle thermogenesis and metabo- fever, and rapid heart rate. Additional complications in se- lism. Compr Physiol 7:879-890, 2017. vere cases may include rapid breakdown of skeletal muscle Rekling JC, Funk GD, Bayliss DA, et al: Synaptic control of motoneu- (rhabdomyolysis) and a high plasma potassium level due ronal excitability. Physiol Rev 80:767, 2000. 7 to release of large amounts of potassium from damaged Rosenberg PB: Calcium entry in skeletal muscle. J Physiol 587:3149, 2009. muscle cells. Treatment of malignant hyperthermia gener- Ruff RL, Lisak RP. Nature and action of antibodies in myasthenia ally involves rapid cooling and the administration of dant- gravis. Neurol Clin 36:275-291, 2018. rolene, a drug that antagonizes ryanodine receptors, which Ruff RL: Endplate contributions to the safety factor for neuromuscular inhibits calcium ion release for the sarcoplasmic reticulum transmission. Muscle Nerve 44:854, 2011. and thereby attenuating muscle contraction. Sine SM: End-plate acetylcholine receptor: structure, mechanism, pharmacology, and disease. Physiol Rev 92:1189, 2012. Tintignac LA, Brenner HR, Rüegg MA. Mechanisms regulating neuro- * dantrolene-> block inhibits RYR > or Bibliography muscular junction development and function and causes of muscle wasting. Physiol Rev 95:809-852, 2015 event resea Also see the bibliography for Chapters 5 and 6. Vincent A: Unraveling the pathogenesis of myasthenia gravis. Nat Rev Bouzat C, Sine SM. Nicotinic acetylcholine receptors at the single- Immunol 10:797, 2002. channel level. Br J Pharmacol 175:1789-1804, 2018. 100