Neuromuscular Physiology

Author(s): Michael K. Mallow, MD

Originally published:11/05/2012

Last updated:10/03/2016

1. OVERVIEW AND DESCRIPTION

The neuromuscular junction acts as an intermediary between the peripheral nervous system and muscle tissue. The small current transmitted by motor axons is transferred into a chemical signal that then triggers a propagating action potential in the much larger muscle tissue. This complicated system is mediated by three specific structures or areas: the presynaptic region, the synaptic space, and the postsynaptic region.1 Abnormalities in these areas, due to disease or exposure to drugs or toxins, can produce the clinical picture of weakness or tetany, and potentially, disability. Impaired neuromuscular transmission can also affect multiple body systems and functions including eye movements, swallowing function, and autonomic function. Medications such as Botulinum toxin can be utilized to purposely impair neuromuscular transmission at the presynaptic terminal while other medications block transmission at the postsynaptic terminal and are utilized in anesthesia to produce paralysis.

2. RELEVANCE TO CLINICAL PRACTICE

Normal neuromuscular transmission can be conceptualized as occurring as a number of steps in a sequence. In actuality, many of the following steps occur at the same time as continued transmission occurs. The neurotransmitter acetylcholine (Ach) is packaged into synaptic vesicles in the presynaptic nerve terminal, the distal aspect of the motor axon, which lies approximately 25nm from the muscle membrane.2 These vesicles cluster in a region of the presynaptic terminal known as the active zone. A large number of acetylcholine-filled vesicles are available for rapid release, and many more vesicles remain in a secondary store. After a single nerve action potential, approximately 200 vesicles of acetylcholine, or quanta, are released, each containing approximately 5000 molecules of acetylcholine.2Docking of these vesicles, and therefore release of acetylcholine is largely dependent on the influx of calcium into the presynaptic terminal. This influx of calcium through voltage-gated calcium channels is triggered by the nerve action potential. The released acetylcholine molecules traverse the short synaptic space and bind to acetylcholine receptors in the postsynaptic region. These receptors are located on a large number of clefts formed by post-junctional folds of postsynaptic muscle cell membrane.1 Binding to the acetylcholine receptor allows sodium to move into the muscle cell, changing the resting membrane potential enough to achieve an muscle action potential and subsequent muscle contraction. Acetylcholinesterase is located in the synaptic cleft and functions to rapidly hydrolyze acetylcholine into acetate and choline. Given the relative number of receptors and the amount of acetylcholinesterase available in the synaptic space, at least 50% of acetylcholine molecules interact with an acetylcholine receptor. In a resting state, a small amount of Ach is continuously released from the presynaptic terminal. An overabundance of acetylcholine molecules provides a safety factor that ensures that a nerve impulse will ultimately result in a muscle action potential.

Normal neuromuscular transmission can be impaired due to abnormalities in several of the steps described above. In the most commonly encountered disorder of neuromuscular transmission, Myasthenia Gravis, antibodies directed against the acetylcholine receptor are present.3 These antibodies render the receptors unavailable for acetylcholine and therefore limit the influx of sodium ions into the muscle cell. In significant disease, this sodium influx may not reach the threshold for muscle action potential. The presence of acetylcholine in the synaptic cleft is extremely short, given the effectiveness of acetylcholinesterase. In these situations, drugs such as Edrophonium and Pyridostigmine can be used to inhibit acetylcholinesterase and provide diagnostic information or improve function.

Calcium influx into the presynaptic terminal occurs via P/Q type calcium channels that are located near the areas of vesicle aggregation, the active zones.1 When an action potential reaches the presynaptic area, sodium enters the presynaptic terminal and, subsequently, calcium channels are activated allowing calcium influx. Vesicles in the active zone bind to the docking proteins, described below, and exocytosis of acetylcholine can take place. Impairment of this calcium influx due to antibodies directed against the P/Q type calcium channel forms the physiologic basis of Lambert-Eaton myasthenic syndrome.4 In normal neuromuscular transmission, calcium influx is limited by voltage-gated potassium channels that allow potassium to be released from the cell as calcium influx occurs. The efflux of potassium ultimately reverses the membrane potential and closes the calcium channels, stopping calcium influx. Potassium channel blockers can be utilized to slow potassium release and, therefore, prolong the calcium influx, increasing the amount of vesicle exocytosis.

The key step of vesicle docking, and ultimate exocytosis, in the presynaptic terminal, is mediated by membrane proteins termed SNAREs, soluble N-ethylmaleimide-sensitive attachment protein receptors. Synaptobrevin, located on the vesicle itself, when exposed to calcium, attaches to syntaxin and SNAP-25 which are located on the internal aspect of the presynaptic plasma membrane. Formation of this complex allows vesicle exocytosis.1This mechanism is relevant clinically as Botulinum toxin A cleaves SNAP-25 and botulinum toxin B cleaves synaptobrevin.

Assessment of patients with potential disorders of neuromuscular transmission is made easier through an understanding of the physiology of the neuromuscular junction. Patients will commonly present with weakness in both Myasthenia Gravis and Lambert-Eaton syndrome; however, given the different pathophysiology described above, patients may exhibit different patterns of weakness. With repeated attempted contraction, more calcium will enter the presynaptic terminal. In Lambert-Eaton syndrome, such influx will improve the patient’s weakness and their strength. In contrast, strength in Myasthenia Gravis may be relatively normal at the outset but is described as, and can be shown to be, fatigable. Continued attempt at contraction, of the eyelid for example, will utilize the available acetylcholine receptors and subsequent attempts at neuromuscular transmission will be unsuccessful.

The neuromuscular junction is commonly assessed electrophysiologically through the use of specific tests, such as repetitive stimulation and single-fiber electromyography (EMG). During repetitive stimulation at slow rates (2-3 Hz), the number of acetylcholine receptors available for attachment by acetylcholine is decreased from one stimulation to the next. Normally the safety factor is large enough to overcome this and all stimulations will lead to a muscle action potential.5 In the case of Myasthenia Gravis, some stimulations will not create an action potential and subsequently a detrimental response of the recorded compound muscle action potential, a summation of many individual muscle action potentials, will be seen. Repetitive stimulation at high rates, on the other hand, will increase the amount of calcium in the nerve terminal. Low rates of stimulation do not cause this increased level, as the calcium quickly disperses. In disorders of impaired vesicle release, botulism and Lambert-Eaton syndrome, fast repetitive stimulation will lead to more acetylcholine available for binding to acetylcholine receptors and subsequently increase successful neuromuscular transmission, seen as an increment in amplitude with successive stimulation.6 Edrophonium, a short-acting anticholinesterase, can also be used to assess for objective improvements in Myasthenia Gravis symptoms. This test should be done with monitoring equipment and where resuscitation is available.1

Knowledge of neuromuscular transmission is essential to provide care of those with neuromuscular disorders, as many will require inpatient rehabilitation after their acute illness. It is also crucial to understanding several specific treatments for spasticity. Botulinum toxin ultimately impairs neuromuscular transmission by binding to the presynaptic terminal and entering the presynaptic terminal through endocytosis. Once intracellular, Botulinum toxin cleaves the membrane docking proteins and prevents acetylcholine exocytosis. Botulinum toxin A cleaves SNAP 25 while Botulinum toxin B cleaves synaptobrevin to limit exocytosis.7

3. CUTTING EDGE/UNIQUE CONCEPTS/EMERGING ISSUES

Critical illness myopathy is an increasingly common source of debility in the hospitalized patient. In critical illness, an up-regulation of immature acetylcholine receptors can be seen.8 These immature receptors have a longer open time than the mature version. These immature receptors with a prolonged open time could potentially explain weakness in critical illness myopathy as long mean open time is associated with weakness and atrophy in other conditions such as congenital myasthenic syndromes; however, this idea is disputed.9 The connection between increased relative numbers of immature acetylcholine receptors in critical illness is an area of research directed at a potential therapeutic solution.

4. GAPS IN KNOWLEDGE/EVIDENCE BASE

The physiology of the neuromuscular junction is important not only in diseases of this region, but in other diseases including critical illness, discussed above, and Amyotrophic Lateral Sclerosis (ALS). Neuromuscular junction degeneration and loss is known to occur in ALS, but the exact mechanism and sequence is unknown and the focus of further research.10Also, in a more general sense, further study of rehabilitation and exercise protocols for those with a disability from disorders of neuromuscular transmission will improve care of these patients.

REFERENCES

  1. Amato A, Russell JA. Neuromuscular Disorders. New York: McGraw Hill Medical; 2008.
  2. Sudhof TC. The synaptic vesicle cycle. Annu Rev Neurosci. 2004;27:509-547.
  3. Lang B, Vincent A. Autoantibodies to ion channels at the neuromuscular junction. Autoimmun Rev. 2003;2(2):94-100.
  4. Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011;10(12):1098-1107.
  5. Ruff RL. Endplate contributions to the safety factor for neuromuscular transmission. Muscle Nerve. 2011;44(6):854-861.
  6. Chiou-Tan FY. Electromyographic approach to neuromuscular junction disorders repetitive nerve stimulation and single-fiber electromyography. Phys Med Rehabil Clin N Am. 2003;14(2):387-401.
  7. Gracies JM, Elovic E, McGuire J, Simpson DM. Traditional pharmacological treatments for spasticity. Part I: Local treatments. Muscle Nerve Suppl. 1997;6:S61-S91.
  8. Ibebunjo C, Nosek MT, Itani MS, Martyn JA. Mechanisms for the paradoxical resistance to d-tubocurarine during immobilization-induced muscle atrophy. J Pharmacol Exp Ther. 1997;283(2):443-451.
  9. Ibebunjo C, Martyn JA. Fiber atrophy, but not changes in acetylcholine receptor expression, contributes to the muscle dysfunction after immobilization. Crit Care Med. 1999;27(2):275-285.
  10. Krakora D, Macrander C, Suzuki M. Neuromuscular junction protection for the potential treatment of amyotrophic lateral sclerosis. Neurol Res Int. 2012; Article ID 379657, 8 pages. doi:10.1155/2012/379657.
  11. Cup EH, Pieterse AJ, Ten Broek-Pastoor JM, et al. Exercise therapy and other types of physical therapy for patients with neuromuscular diseases: a systematic review. Arch Phys Med Rehabil. 2007;88(11):1452-1464.

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Michael K. Mallow, MD. Neuromuscular Physiology. Publication Date: 2012/11/05.

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