Are Continuous With Cell Membrane Conducts Action Potentials Deep Into the Muscle Fiber

Muscle Fiber Membrane

Muscle fiber membranes appear to have fewer chloride channels than normal, resulting in decreased chloride conduction across the membrane, with subsequent increased membrane excitability and repetitive firing (Smith and Sherman, 1994).

From: Laboratory Animal Medicine (Second Edition) , 2002

Structure and Function of Skeletal Muscle

Samantha C. Salvage , ... Christopher L.-H. Huang , in Encyclopedia of Bone Biology, 2020

Action Potential Repolarization Involves K⁺ Channel Activation and Cl⁻ Channel Effects

Muscle membranes similarly express a K⁺ channel type that is activated by depolarization over a timecourse that resembles that found in nerve membranes. This contributes, together with Na⁺ channel inactivation and the background Cl⁻ conductance, to the initial falling phase of the muscle action potential. Thus, voltage-clamp experiments investigating the existence and identity of membrane currents first demonstrated in invertebrate axons have been adapted to similar studies in skeletal muscle (Adrian et al., 1970) (Fig. 10A ). These have demonstrated the characteristic early rapid increasing then inactivating inward Na⁺ and more gradually developing outward K⁺ currents (Fig. 10B). These accordingly mediate the rapid depolarizing and repolarizing phases of the action potential which followed models assuming voltage-dependent activation and inactivation processes governing channel gating (Fig. 8).

Skeletal muscle contains further time and voltage-dependent K⁺ current types. In addition to the voltage gated K⁺ channel which is activated ~ 5–10 ms following Na⁺ channel opening, a second K⁺ channel type is activated over a considerably longer timecourse of hundreds of ms. Finally, a voltage-insensitive inward rectification channel allows potassium to pass more easily into than out of the cell thereby minimizing leak currents needed to sustain a given membrane potential. It may contribute the greater part of the K⁺ conductance that maintains the resting potential (Adrian, 1969). Resting skeletal muscle cells also show a significant Cl⁻ conductance that stabilizes the membrane potential between episodes of electrical activity (Ferenczi et al., 2004; Pedersen et al., 2016).

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Neuromuscular Physiology and Pharmacology

Edward A. Bittner , J.A. Jeevendra Martyn , in Pharmacology and Physiology for Anesthesia (Second Edition), 2019

Postsynaptic Membrane

The muscle membrane is highly corrugated with deep invaginations representing primary (shallower) and secondary (deeper) clefts such that the total surface area of each endplate is very large (see Fig. 21.1). The depths of these folds vary between muscle types and species. The shoulders of the folds contain high densities of AChRs (~ 5 million in each junction) anchored into the muscle cell membrane by a complex system of cytoskeletal proteins. AChRs are sparse in the depths between the folds, which contain a high density of voltage-gated Na⁺ channels for amplification of AChR-induced depolarization.

The perijunctional zone is the area of muscle that lies immediately beyond the junctional area. It serves the critical function of transducing the signal from the junction into deeper regions of the muscle cell. The perijunctional zone contains a high density of Na⁺ channels that promote amplification of the transduced signal, culminating in muscle contraction. The density of Na⁺ channels in the perijunctional zone is greater than in more distal parts of the muscle membrane. ¹² Furthermore, specific isoforms of AChRs and Na⁺ channels are expressed in the perijunctional area at different stages of life and during pathologic conditions that decrease nerve activity. Mutations in AChRs and Na⁺ and Ca²⁺ channels in this area have been identified. ^13,14 For example, in hypokalemic periodic paralysis, characterized by episodes of severe flaccid muscle paralysis, the muscle fiber membrane becomes electrically inexcitable, which can be precipitated by low serum K ⁺ levels. This pathologic state is the archetypal skeletal muscle channelopathy caused by dysfunction of specific sarcolemmal Na⁺ or Ca²⁺ ion channels. ¹⁵ These variations in receptors and channels contribute to differences in response to neuromuscular drugs observed in different age groups and pathologic conditions. ^16,17

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Disorders of Muscle Excitability

Juan M. Pascual , Scott T. Brady , in Basic Neurochemistry (Eighth Edition), 2012

The excitable apparatus of muscle is composed of membranous compartments

The muscle cell membrane, together with connective tissue elements and collagen fibrils, forms the sarcolemma (Franzini-Armstrong, 1979). The interior of the resting cell is maintained at an electrical potential about 80 mV more negative than the exterior by the combined action of pumps and channels and the solutions bathing the membrane. Unlike nerve membranes, muscle membranes possess a high conductance (G) to chloride ions in the resting state such that G_Cl- accounts for ~70% of the total membrane conductance. Potassium ion conductance accounts for most of the remainder, such that the membrane potential is normally close to the Nernst potential for these two ions (see Ch. 4). Asymmetrical concentration gradients for sodium and potassium ions are maintained at the expense of energy consumed by the membrane Na⁺/K⁺-ATPase. During the generation of a muscle action potential, a rapid and stereotyped membrane depolarization is produced by an increase in sodium ion conductance mediated by voltage-dependent Na⁺ channels. The sodium conductance increase is self-limited due to channel inactivation, and membrane repolarization is also assisted by the delayed opening of potassium channels. Action potentials originating at the NMJ spread in a nondecremental fashion over the entire surface of the muscle and penetrate the interior of the muscle cell along transverse (T) tubules that are continuous with the outer membrane (Fig. 44-4). These tubules convey sarcolemmal depolarization to the center of the muscle fiber very effectively. As the T-tubular network extends inward into the cell, close associations are formed with specialized terminal elements of the sarcoplasmic reticulum (SR). At the electron microscope level of observation, the structure formed by a single tubule interposed between two terminal SR elements is called a triad. The SR stores Ca²⁺ in relaxed muscle and releases it into the sarcoplasm upon depolarization of the membrane of the T-tubular system.

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DISORDERS OF SKELETAL MUSCLE

Rodger Laurent , in The Musculoskeletal System (Second Edition), 2010

The muscle fibre

Muscles are made up of a collection of individual muscle fibres (Figs 8.1, 8.2). Each fibre is a multinucleated cell, which can be up to 10 cm in length with a diameter ranging from 10–100 μm. Normal muscles have the nuclei arranged around the periphery of the cells.

The muscle cell membrane is called the sarcolemma and the cytoplasm, the sarcoplasm. The sarcolemma has the property of excitability and can conduct the electrical impulses that occur during depolarization. A system of tubules, the transverse tubules or T-tubules, begins at the sarcolemma and extends into the sarcoplasm. They allow rapid distribution of the signal to contract throughout the muscle fibre.

Case 8.1

Myopathy: 1

Case history

Mr Colin Brown is a 47-year-old man who presents to his general practitioner complaining of weakness in both legs when getting out of a chair. He first noticed muscle weakness about 6 months earlier, when he had difficulty walking up and down the stairs at work. He also noticed that his arm and leg muscles were often painful after exercise and occasionally his thigh muscles would be tender. Over the last 2 months, he has noticed increased tiredness.

The history raises the possibility of a disorder of skeletal muscle. It would be important to consider what other clinical information is required and what should be specifically looked for on physical examination.

The muscle fibre contains numerous myofibrils, which are 1–2 μm in diameter and the length of the cell (Fig. 8.1A). Myofibrils shorten and are the structures responsible for muscle contraction. They shorten the fibre because they are attached to the sarcolemma at each of its ends. Mitochondria and glycogen granules are situated between the myofibrils.

The myofibrils consist of bundles of filaments, which are made up of the proteins actin and myosin, and are organized in repeating functional units called sarco-meres. Sarcomeres are the smallest functional units of the muscle fibre (Fig. 8.1C). The actin filaments are thin and the myosin filaments are thick. The thick filaments lie at the centre of the sarcomere with the thin filaments at either end. On either side of the centre, there is an area of overlap between the thin and thick filaments in which each myosin filament is surrounded by a hexagonal array of actin filaments. The arrangement of the myosin and actin filaments gives a banded appearance to the muscle and is the reason it is called striated muscle. The sarco-meres are separated by a dense area called the Z line. The M line is at the middle of the sarcomere and consists of proteins that bind the thick myosin filaments. The actin and myosin filaments are joined by molecular cross-bridges and, during contraction, these cross-bridges repeatedly disengage and engage at successive sites, with the result that the actin and myosin filaments slide upon one another and the myofibrils shorten.

The myofibril is surrounded by a sheath of membranes called the sarcoplasmic reticulum. At the zone of overlap between the thick and thin filaments, the tubules of the sarcoplasmic reticulum enlarge and form chambers called terminal cisternae. A transverse tubule is situated between two terminal cisternae and the resulting complex is called a triad. The cisternae contain large stores of calcium ions. Release of calcium from these structures initiates the muscle contraction.

The size of the muscle varies in proportion to the size of the fibres with larger fibres being present in larger muscles. Consistent physical exercise can increase the muscle fibre diameter in both sexes.

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Single-Fiber Electromyography and Other Electrophysiologic Techniques for the Study of the Motor Unit

ERIK V. STÅLBERG , JOŽE V. TRONTELJ , in Peripheral Neuropathy (Fourth Edition), 2005

Direct Stimulation

To study muscle fiber membrane parameters, the muscle fiber is stimulated directly. The evidence of direct muscle fiber stimulation is a jitter less than 4 μs, generated mainly at the stimulus site. However, with threshold stimulation, the jitter may be very large and the mean latency longer. ⁵⁹ Even when intramuscular stimulation is performed close to the end-plate zone for a jitter study, part of the responses may be due to direct stimulation.

Direct muscle fiber stimulation has been used in studies of denervated muscles ⁵⁵ and in myopathies. ¹⁷ Patients with myotonia congenita (Thomsen and Becker types) showed a pronounced decrement of action potential amplitude and changes of shape during stimulation at 2 to 20 Hz. The findings were interpreted as signs of a disturbed depolarization-repolarization cycle. In addition, signs of focal conduction block of action potentials were found in some fibers. This is also found in studies with surface EMG. ⁵ Both mechanisms may contribute to the myotonic weakness.

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The chemical synapses

Constance Hammond , Monique Esclapez , in Cellular and Molecular Neurophysiology (Fourth Edition), 2015

6.3.2 The synaptic cleft is narrow and occupied by a basal lamina which contains acetylcholinesterase

The postsynaptic muscular membrane (sarcolemma) is covered, on the extracellular surface, with a layer of electron-dense material, the basal lamina ( Figure 6.12 a,c). This lamina, which follows the folds of the sarcolemma, is a conjunctive tissue secreted by the non-myelinating Schwann cells covering the axon terminals. It contains, inter alia, collagen, proteoglycans and laminin.

Acetylcholinesterases are glycoproteins synthesized in the soma and carried to the terminals via anterograde axonal transport. They are inserted into the presynaptic membrane and the basal lamina. They display an important structural polymorphism ( Figure 6.12 b): they have a globular form (G) or an asymmetric form (A). These different forms have distinct localizations. Globular forms (G) are anchored in the pre- or postsynaptic membrane (these are ectoenzymes) and are secreted as a soluble protein into the synaptic cleft. Asymmetric forms (A) are anchored in the basal lamina ( Figure 6.12 c). The molecules of acetylcholine, released in the synaptic cleft when the neuromuscular junction is activated, cross the basal lamina through its loose stitches. But a part of the acetylcholine molecules is also degraded before being fixed to postsynaptic receptors, by the acetylcholinesterase inserted in the basal lamina. The other part is quickly degraded after its fixation. Acetylcholinesterases hydrolyze acetylcholine into acetic acid and choline. Choline is taken up by presynaptic terminals for the synthesis of new molecules of acetylcholine. This degradation system of acetylcholine is a very efficient system for inactivation of a neurotransmitter.

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Ion Channels Across Cell Membranes

Wilfred D. Stein , Thomas Litman , in Channels, Carriers, and Pumps (Second Edition), 2015

3.6.2 Sodium and Potassium Channels of Excitable Tissue

Nerve and muscle cell membranes contain numerous voltage-sensitive channels that are selective for sodium or for potassium ions. Their sequential opening and closing in response to the prevailing transmembrane potential is the basis for the propagation of the nerve signal along the axon and its spread across the muscle membrane. The sodium channel, in particular, has been well characterized, isolated, cloned, sequenced, and reconstituted into artificial phospholipid membranes. It is a single polypeptide chain of approximately 260,000-Da molecular mass. It is built of four repeating units, each rather similar to one of the subunit polypeptides of the nAChR channel that we discussed in Section 3.2. Each repeating unit is itself composed of six membrane-spanning stretches. One of these in each unit has the remarkable structure of a five- to sevenfold repeat of the triplet (–Arg–X–X–), where Arg (sometimes replaced by Lys) is the positively charged amino acid arginine (or lysine) and X is a hydrophobic residue. It is thought that this stretch of amino acids senses the voltage that gates (see Section 3.2) the sodium channel. Remarkably, the amino acid sequence of the sodium channel is similar to those of two other voltage-gated channels, a calcium channel and a potassium channel (see Box 3.8). It seems that, just as we saw in Section 3.2 for the chemically gated channels, there is a family of voltage-gated channels. There seems to be no common ancestry between the voltage-gated and the chemically gated channels (Box 3.6).

Box 3.6

Molecular Biology, Evolution, and Structure of the Ion Channels

The genes coding for a voltage-gated sodium channel from eel for a calcium channel and potassium channel from the fly were the first to be cloned and sequenced by a variety of interesting methods (see the classic studies—Noda et al., Tanabe et al. and Papazian et al.—in the section on "Suggested Readings") as we go on to discuss. Since these pioneering studies, the sequences of hundreds of ion channels are now known, leading to stimulating ideas about their evolution. The molecular structure of many channels has been determined and their physiological function interpreted at the molecular level.

Early Studies on Cloning and Sequencing Ion Channels

First cloned, in 1984, in the laboratory of Shosaku Numa, was the gene for the sodium channel from the electric eel, Electrophorus electricus. A toxin from scorpions, the α-toxin, binds with high affinity to nerve cell membranes, blocking the passage of the sodium current. This fact made possible the isolation of the sodium channel protein from detergent-solubilized membranes of the electric organ of the eel by identifying a protein in the membrane extract that bounds the neurotoxin. Peptides were prepared from the sodium channel protein, by digestion with the enzyme trypsin. DNA sequences were then constructed that were possible coding sequences for certain of those peptides. cDNA clones were grown containing the sequences complementary to the messenger RNA from the electric organ cells. Antibodies were prepared (in rabbits) against the sodium channel protein, and the cDNA clones were screened to identify which produced proteins that reacted with the antibody to the known sodium channel. Four such clones were found and tested by hybridizing them against the DNA sequences constructed on the basis of the peptide digests. One clone proved positive, i.e., it coded for a known portion of the sodium channel gene. But how were the researchers to locate the sequence that coded for the whole protein? DNA prepared from the identified clone was then used to search for sequences that overlapped with an end of its sequence, and those sequences were used, in turn, to search for sequences that overlapped with them. In this way, by extending out in both directions from the single original clone, DNA sequences composing the whole of the gene for the sodium channel were identified.

The bottom row of Figure 3.13A depicts the arrangement of the polypeptide chain of the channel within the cell membrane, as deduced from hydropathy plots. (Refer to Section 1.5 for more on hydropathy plots.) There are four regions each built up of six putative membrane-spanning sequences; the four regions are closely homologous with each other in their sequences. The red-shaded sequence in each region is the S4 sequence containing the repeating –Arg(or Lys)–X–X– triplet, the three or four positive charges that comprise the voltage-sensing element of the region, as had been suggested many years ago on the basis of electrophysiological experiments.

Next to be cloned, in 1987, again by Numa and colleagues, was a calcium channel. Of the numerous types of calcium channels, one is blocked by the drug dihydropyridine and, as in the sodium channel just discussed, the presence of such an effective channel-blocking substance led to the isolation of a protein that bound dihydropyridine, the preparation of peptides from the protein, and the eventual cloning of the gene coding for the protein. Its sequence was found to be strikingly similar to that of the sodium channel, with the same pattern of four homologous regions, each containing six putative membrane-spanning stretches with many of the unique arginine-containing repeating sequences preserved in the S4 stretch. It has been shown that microinjection, into the cell nucleus, of a plasmid containing the DNA that codes for this calcium channel leads to the expression of calcium channel activity in the cell membrane. (In order to prove that this channel activity arose from the plasmid, the cells chosen as the expression system were muscle cells taken from rats that were suffering from muscular dysgenesis, in which such calcium channel activity is defective!)

Drugs that block potassium channels with high affinity have been harder to find, and this fact had hindered the isolation of potassium channels. Methods other than the use of known peptide sequences had to be developed to allow the gene for a potassium channel to be identified in DNA clones. Also in 1987, Diane Papazian, Bruce Tempel, and colleagues used the technique known as "chromosome walking." They took advantage of the fact that the mutation Shaker in Drosophila results in a defect in a potassium channel. (Shaker mutants are so called since their legs shake when the mutant flies are anesthetized.) The gene has been located by gene mapping at a particular point on the X chromosome (band 16F). A sequence of DNA that bound to the X chromosome in this region had been identified. Using this sequence, a "walk" was made in both directions along the chromosome by finding DNA sequences, cloned from the fly's genome, that overlapped with the ends of the sequence known to bind in the 16F region. The DNA clones so identified were then tested against DNA prepared from mutant flies in which the Shaker gene had suffered a deletion. In this way clones coding for the Shaker gene product could be identified as those that were not present in the mutant flies. Sequencing those clones gave the structure shown in Figure 3.13A (bottom). The sequence predicts a structure that is one-quarter of the size of the sodium and calcium channels, very similar to one of the four homologous regions in those channels. Expression in frog oocytes of the messenger RNA transcribed from the putative potassium channel DNA gave rise to potassium channels in the oocyte membranes. A large number of different potassium channels have now been cloned from the fly, many with the same general structure as that depicted in Figure 3.13A (bottom). These different channel proteins may be responsible for the variety of potassium channels that the fly seems to possess.

Evolution of the Ion Channels

(This section is based on and, with permission, quotes extensively from a fine review, by Harold Zakon—see Zakon HH, Adaptive evolution of voltage-gated sodium channels: the first 800 million years. Proc Natl Acad Sci USA. 2012; 109: 10619–25, which should be consulted for further details.)

The potassium channel is clearly the simplest of the three that we have been discussing. It appears that potassium channels arose first in evolution, being found in bacteria, unlike calcium and sodium channels. Voltage-gated ion channels (we write them here with a subscript v) are the basis of electrical excitability of all animals and many single-celled eukaryotes. Potassium leak and voltage-dependent K⁺ (K_v) channels appeared three billion years ago in bacteria and occur in all organisms (Figure 3.13B). They establish resting potentials, and repolarize membranes, after excitatory events. K_v channels are the "founding members" of the family of ion-permeating channels whose basic structure is a polypeptide chain of six transmembrane helices (6TM) that associate as tetramers to form a channel (Box 3.8). At some point early in eukaryote evolution, the gene for a 6TM channel likely duplicated, giving rise to a protein with two domains. These proteins then dimerized to form a complete channel. Such a channel still exists in the two-pore channel family of Ca²⁺-permeable channels localized in endosomes and lysosomes. The gene for a two-domain channel likely duplicated to make a protein with four domains capable of forming a channel on its own (4×6TM). Eventually such four-domain channels evolved (or retained) permeability to Ca²⁺ and these handily became involved in intracellular signaling.

Na_v channels share the 4×6TM structure (Figure 3.13A) with Ca_v channels, and it has been suggested that Na_v channels evolved from Ca_v channels. Analysis of putative Ca_v and Na_v channel genes from fungi, the early multicellular organisms, the choanoflagellates, and metazoans confirms this speculation. The selectivity filter of 4×6TM channels depends on a single amino acid in each of the four domains that come together and face each other, presumably forming the deepest point in the pore. The selectivity filter of the choanoflagellate and other basal metazoans (sequence DEEA) is midway between bona fide Ca_v (EEEE) and Na_v1 (DEKA) channel pores. Evolution of the metazoans proceeded with further evolution in the direction of this new specificity toward sodium and the appearance of sodium-specific channels, these still bearing the four-region motif. Approximately 500 Mya (million years ago) in early chordates (vertebrates, tunicates, and cephalochordates) Na_v channels evolved a motif that allowed them to cluster to form axon initial segments. Clustering enabled the point of cluster to be a sufficient source of local reversal of membrane potential to be recognizable as a signal that could then be propagated to adjacent cells. Note that both these two properties had to evolve to make the sodium channels useful as nerve precursors—the favoring of sodium over calcium and, in addition, the ability to cluster; 50 million years later with the evolution of myelin, Na_v channels "capitalized" on this second property and clustered at nodes of Ranvier. The resultant enhancement of conduction velocity (greatly enhancing the speed of reaction to stimuli) along with the evolution of jaws likely made early gnathostomes (the jawed fishes and later vertebrates) fierce predators and the dominant vertebrates in the ocean.

Myelination and saltatory conduction (saltatory: proceeding by leaps) are key innovations of the vertebrate nervous system that markedly increase axonal conduction. Saltatory conduction depends on high densities of Na_v channels at the nodes of Ranvier that inject sufficient current into the axon to depolarize the adjacent node to threshold (thus leaping toward it). KCNQ-type K⁺ channels, which help to repolarize the action potential, cluster at nodes as well, both channels tethered to ankyrin (see Figure 1.9) and thence to the cytoskeleton. Remarkably, both Na_v and KCNQ K⁺ channels evolved the same specific nine amino acid motif for ankyrin binding.

Molecular Structure of the Voltage-Gated Channels

Solving the structure of many of the ion channels has, of course, added enormous depth to our understanding of how such channels work. We can take up here only one example of such studies and our choice has fallen on the mechanism of voltage activation of the sodium channels. We mentioned above that it is a series of positively charged arginines that appeared to be the voltage sensing domain (VSD) of both the potassium and the sodium channels. Catterall's group described four such arginines on successive loops of segment S4 of the protein (Figure 3.14…find R1, R2, R3, and R4 in the structures depicted) in their initial report on the molecular structure of a sodium channel (Payandeh, Scheuer, Zheng, and Catterall, The Crystal Structure Of A Voltage-Gated Sodium Channel. Nature. 2011; 475: 353–358), and such structures have since been found in other voltage-gated channels.

The presence of these four arginines beautifully accorded with what the physiologists had found. But how were the Catterall group to elucidate the structural change? The problem was that the structures that had been solved were of the voltage-activated form, necessarily—since they were derived using crystals that were not situated in a gradient of electrical potential. In contrast, the resting state of the sodium channels is found when there is a negative-inside transmembrane potential. To model the resting state, Catterall and his colleagues used a combination of methods: structure determination on a simpler system, NaChBac, a bacterial sodium channel; genetic engineering of mutants possessing designed cysteine/cysteine bridges that would stabilize presumably intermediate conformations of the channels; expressing these mutants in cells in culture and performing electrophysiological experiments on the cells to check whether or not the mutants were responsive to the transmembrane voltage; modeling all these channels in Rosetta, a program which determines the energetic state of various conformations of a protein, so that the states of lowest energy (and hence most likely to be present) can be identified. This tour de force identified a structure that appeared to be a good candidate for the sodium channel's resting state, depicted as the left-hand models in Figure 3.14 (closed). Note that in this state the four arginines that straddle the brown-shaded region marked as HCS (hydrophobic constriction site) largely lie below this region, while in the activated state (on the right), they lie largely above this region. The HCS is a region composed mainly of hydrophobic groups which do not bond with the arginines, nor impede their sliding past, and allow movement of R1 through R4 from the intracellular to the extracellular faces without any ion leak. Note in these models how the residue E43 is free in the resting state but bonded to R1 and R2 (which had been buried within the HCS region) in the activated state. Numerous other changes in bonding patterns can be seen on comparing the two states. Figure 3.14B emphasizes a crucial point: The sliding of R1 through R4 across HCS would be of little significance by itself, but segment S4 continues into segment S5. As S4, with the change from resting to activated state, rotates about an axis perpendicular to the plane of the membrane, it drags S5 with it and this in turn drags with it the subsequent connected segments, bringing about the opening of the sodium channel. The transition depicted in Figure 3.14 is thus a molecular explanation of the voltage-induced gating of the ion channels.

One should note, however, that, convincing as this work seems to be the resting state has not been "seen" directly and we will not have the final picture until a way is found to manipulate the electric field across such crystals.

How do the properties of the sodium channel and the potassium channel account for the propagation of the nervous impulse? Consider the model in Figure 3.15, showing a nerve cell membrane that contains a voltage-sensitive sodium channel, a voltage-sensitive potassium channel, and another, unspecified but voltage-insensitive, pathway for potassium movement. In the uppermost picture, both voltage-sensitive channels are switched off. The membrane is in a "resting state" in which its permeability is low absolutely but relatively high for potassium ions. The membrane potential, as we saw in Table 3.2, is determined largely by that ion whose permeability dominates, in this case, by the potassium ions, and the measured resting membrane potential is, indeed, about −60 mV. If now the membrane potential is suddenly altered to inside positive (Figure 3.15B) (how this happens will become clear in a moment), the voltage-sensitive sodium channel is switched on. The permeability of sodium now becomes dominant, and the membrane potential will be given by the ratio of sodium concentrations. These are low inside, high outside. This is how the potential reverses, becoming positive inside, as the sodium ions tend to rush in down their concentration gradient. Figure 3.10 is a record of such an "action potential," the changes in membrane potential that occur as the impulse passes a point on the nerve cell membrane. (In Box 3.7, we calculate how many sodium ions need to flow into the cell in order to reverse the membrane potential.) This change in potential has two effects. One effect is to switch on the next adjacent sodium channel (Figure 3.15C). In this way, a progression is achieved, a channel switching on an adjacent channel to propagate the signal down the axon. The other effect of the reversal of potential is to switch on the potassium channel. This is switched on with a delay and, responding to the ambient concentrations of potassium, restores the membrane potential to its original direction, inside negative (Figure 3.15D)! The signal does not propagate in the reverse direction because any switching on of the sodium channel is overwhelmed by the potassium permeability that has been enhanced over that in the resting membrane. Therefore, the switching on of the potassium channel ensures that the axon has a refractory period after the impulse passes. Switching on and off of the nerve channels has steeper voltage dependence than that depicted for the potassium channel of the sarcoplasmic reticulum in Figure 3.12. The data are consistent with three or four charges driving the conformation change between the open and closed channels. (This is consistent with the presence of a voltage-sensitive amino acid sequence in each of the four large repeating units in the channel's primary structure, as discussed above.) These charges move with respect to the plane of the membrane, producing a tiny current known as the gating current. This current has been measured during the opening of a sodium channel in the nerve—a technical feat, since the gating current is 1,000 times smaller than the current that flows through the channel itself.

Box 3.7

The Number of Ions Needed to Cross the Membrane in Order to Establish or Change the Membrane Potential

To calculate how many ions need to flow across the membrane in order to set up a particular transmembrane potential, we need first to understand the relation between the electric charge and potential. A substance such as a cell membrane, which is not a good conductor of electricity (as opposed to a copper wire), is known as a capacitor. It can act as an insulator, allowing a separation of electric charge to be established across it under the influence of an applied electrical potential. The charge and membrane potential are related by a quantity known as the capacitance. This is the measure of how much charge needs to be placed on the capacitor in order for it to develop unit potential. If the charge, Q, is measured in coulombs (96,500 C are associated with one mole-equivalent of a monovalent ion), and the potential measured in volts (V), the capacity will be in farads (abbreviated F). Biological membranes have capacitances of size about 1 µF/cm².

Take a typical animal cell of radius about 20 µm or 20×10⁻⁴ cm. This has an area of 4π(20×10⁻⁴)² cm² and a capacity of that number of microfarads. To set up a membrane potential cross it, of the frequently found 60 mV, will require a charge of Q=CV=4π(20×10⁻⁴)²×10⁻⁶×60×10⁻³ C, which is associated with 4π(20×10⁻⁴)²×10⁻⁶×60×10⁻³/≈10⁵ mol or 3×10⁻¹⁷ mol of ion, a very small number. The potassium content of such a cell, when the potassium is present at 140 mM in a volume of 4π(20×10⁻⁴)³/3 cm³, is 4.7×10⁻¹² moles. Thus to charge the membrane to 60 mV requires that as little as 6.4×10⁻⁴ percent of the cell's potassium be transferred across the cell membrane.

This ratio obviously depends on the surface:volume ratio of the cell. Let us calculate this ratio for a typical small axon of radius about 0.1 µm and containing 10 mM of sodium, where the inflow of sodium during the action potential changes the membrane potential from 60 mV inside negative to 60 mV inside positive. For a cylinder of radius r, the area to volume ratio is 2/r. The ratio of the amount of sodium that must be moved in order to reverse the membrane potential, to the amount of sodium present within the cell, is (120×10⁻³×2×10⁻⁶)/(0.1×10⁻⁴×10×10⁻¹)> or 2.4%. This is by no means an insignificant number and requires that the cell possess a very effective method of pumping out the sodium that has entered, if the axon is to maintain its ability to transmit an impulse. (We shall discuss this sodium pump in detail in Section 6.1.)

Box 3.8

Classification of Ion Channels

The more than 300 different channels encoded in the human genome can be classified both according to the type of ion that they are most permeable to, such as sodium, potassium, calcium, or chloride, and according to the gating mechanism, i.e., whether the opening of the channel is regulated by a ligand (LGICs) or by a change in membrane potential (voltage-gated ion channels). Table 3.3 lists the various channel classes (mostly human) as well as representative family members and their characteristics. For a comprehensive classification of membrane transporters, see the Transporter Classification Database at tcdb.org.

Channels can also be categorized according to their evolutionary relationship, based on conservation and sequence similarity, i.e., closely related channels made up of homologous ¹ subunits will cluster together on nearby branches on the evolutionary tree, while distantly or unrelated channels with little sequence similarity will be far apart. A phylogenetic tree showing the relationship between the LGICs is shown below. The tree is based on a multiple sequence alignment of 72 sequences using the COBALT tool at NCBI. All sequences were retrieved from GenBank, and redundant data were excluded (if more than one isotype was found, only the first (isotype 1 or a) was included in the alignment, and only well-annotated RefSeq sequences were used). Note that official HUGO gene names are shown, while the alignment is based on the amino acid sequence. All sequences are human, except for the nAChR subunits labeled as "Torpedo," which are included to illustrate the orthologous nature of these subunits. Here, the corresponding subunits between species (e.g., α1 of human and Torpedo) are more similar to each other than to any other subunits. The tree's main branches are named after the channel families, often synonymous with the main ligand of the receptor: 5-HT, 5-hydroxytryptamine (serotonin; note that this is the 5-HT ₃ ion channel, and not related to the other serotonin receptors, which are all GPCRs); ACh, acetylcholine; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (and glutamate); GABA, γ-aminobutyric acid (note that these receptors are of the GABA_A and GABA_A−ρ (formerly GABA_C) subtype, and not related to the GABA_B receptor, which is a GPCR); GLY, glycine; KAINATE, kainate (and glutamate); NMDA, N-methyl-d-aspartic acid (and glutamate); P2X, adenosine 5′-triphosphate. As seen from the tree, the cys-loop superfamily (ACh, GLY, GABA, and 5-HT) separates from the glutamate (NMDA, AMPA, KAINATE) and ATP (P2X) gated channels, which is expected, since these families are evolutionary unrelated. Interestingly, the 5-HT₃ α-subunit (HTR3A) appears closely related to the nAChR α9 (CHRNA9) and α10 (CHRNA10) subunits, suggesting a common evolutionary relationship. Also, the glycine receptor β-subunit (GLRB) is on the same branch as the GABA receptors, implying an evolutionary linkage.

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Rhabdomyolysis

Susanne E. Tanski MD , in Pediatric Clinical Advisor (Second Edition), 2007

Etiology

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Damage to muscle cell and membrane results in liberation of intracellular contents.

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Many causes exist, including the following:

○: Trauma: blunt trauma, electrical injury, burns, prolonged immobilization
○: Exercise: induction of the syndrome by strenuous exercise
○: Toxins (46% to 80% of cases): alcohol, drugs of abuse, medications (e.g., statins), envenomation
○: Metabolic causes: inborn disorders affecting carbohydrate or lipid metabolism, thyroid dysfunction, diabetic ketoacidosis, electrolyte abnormalities
○: Infections: influenza, human immunodeficiency virus (HIV), herpes simplex virus (HSV), many other viruses and bacterial infections
○: Environmental causes: hyperthermia, hypothermia
○: Muscle abnormalities: myopathies, polymyositis, dermatomyositis

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Electrophysiology: Nerve Conduction Studies and Electromyography

Elizabeth M. Raynor , David C. Preston , in Office Practice of Neurology (Second Edition), 2003

Recording Methods and Normal Findings

The electromyogram (EMG) is a recording of the electrical activity in muscle fiber membranes that provides information about the muscle and related nerves. In a routine examination, a small needle electrode is inserted into various muscles, and activity is observed in a number of sites within each muscle. Findings are observed during needle insertion, with the muscle at rest, and during voluntary contraction. The selection of muscles for study usually is made by the electromyographer based on the clinical question and the prior nerve conduction and EMG findings.

Insertional Activity.

Mechanical deformation of the muscle membrane by the needle normally causes brief discharges lasting less than 500 msec after needle movement ceases. Insertional activity increases in disorders that cause abnormal excitability of muscle membrane, most commonly in neurogenic disorders. Decreased insertional activity results from muscle fibrosis or fatty replacement, which may be present in long-standing muscle disorders such as dystrophies.

Spontaneous Activity.

Normal muscle is silent at rest, except when the needle is in the vicinity of the neuromuscular junction. Here, endplate activity normally may be recorded. This physiologic spontaneous activity is of little importance except that it may be mistaken for abnormal spontaneous activity.

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Muscles

In Cell Biology (Third Edition), 2017

Excitation Contraction Coupling

As in skeletal muscle, plasma membrane action potentials stimulate cardiac muscle cells to contract by releasing cytoplasmic Ca²⁺ to activate troponin-tropomyosin (Fig. 39.14B). Calcium ATPase pumps (see Fig. 14.7) in SER and plasma membrane maintain the low cytoplasmic Ca²⁺ concentration with some help from plasma membrane Na⁺/Ca²⁺ antiporters.

In both cardiac and skeletal muscle action potentials activate L-type voltage-sensitive Ca²⁺ channels (DHP receptors) in T tubules, but subsequent events differ as revealed by a requirement for extracellular Ca²⁺ in heart but not skeletal muscle (Fig. 39.14). Rather than interacting directly with ryanodine receptors as in skeletal muscle, the active cardiac L-type voltage-sensitive Ca²⁺ channels admit extracellular Ca²⁺. This opens nearby ryanodine receptors in the SER, releasing a flood of Ca²⁺ to trigger contraction. This is called calcium-induced calcium release.

Excitation-contraction coupling can be defective when heart muscle cells grow larger in response to abnormal demands, such as high blood pressure. The defect may be explained by growth separating T tubules from SER, either physically or functionally, thereby decreasing the probability that Ca²⁺ entering through DHP receptors will trigger Ca²⁺ release from the endoplasmic reticulum.

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Are Continuous With Cell Membrane Conducts Action Potentials Deep Into the Muscle Fiber

Muscle Fiber Membrane

Structure and Function of Skeletal Muscle

Action Potential Repolarization Involves K⁺ Channel Activation and Cl⁻ Channel Effects