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Physiology, Neuromuscular Transmission

Authors

Sopiko Jimsheleishvili1; Komal Marwaha2; Andrew l. Sherman3.

Affiliations
1 University of Miami Miller School of Med
2 Maharishi University of Managemet
3 Un of Miami Miller School of Med

Last Update: August 10, 2019.

Introduction
Neuromuscular junction (NMJ) is responsible for the chemical transmission of the electrical impulse from a nerve to
the muscle( skeletal/ smooth/ cardiac) in order to produce an appropriate muscle contraction. Diseases of NMJ such
as Myasthenia Gravis, Lambert-Eaton Syndrome, and Botulism affects neuromuscular impulse transmission and result
in muscle weakness and paralysis. Many drugs and anesthetic agents also affect neuromuscular junction and impulse
transmission to elicit their effects. In order to understand the pathophysiology and basis of treatment of the diseases
that affect neuromuscular transmission, it is important to have a thorough knowledge of the structure of NMJ and
physiology of neuromuscular transmission.[1][2][3][2]

Issues of Concern
Failure of or a defect in neuromuscular transmission may occur in a number of disease states. These disease states
produce weakness of muscles of eyes, face, limbs, respiration etc. Though the clinical presentation of these diseases
may appear similar, there are important differences in the etiology and the basis of treatment.[4].

Cellular
Physiological Anatomy of Neuromuscular Junction

The structure of NMJ of a skeletal, smooth, or cardiac muscle vary a little from each other but all have three main
parts; a motor nerve ending, also termed the presynaptic part; postsynaptic part, the motor endplate which is a part of
the muscle membrane; the synaptic cleft; an area between the motor nerve ending and the motor endplate.

Neuromuscular Junction of Skeletal Muscle

A skeletal NMJ is formed between the nerve endings of a motor neuron that arise either from the ventral horn of the
spinal cord or from the medulla and the part of plasma membrane skeletal muscle called motor endplate. On reaching
the target muscle, the myelinated motor neuron loses its myelin sheath to form a complex of 100-200 branching nerve
endings called nerve terminal/ terminal boutons. Each nerve terminal lies against the motor endplate and is covered by
Schwann cells. The nerve terminal is the presynaptic part of skeletal muscle NMJ. Its structure is quite different from
that of the rest of the axon. It has voltage-gated calcium channels and potassium channels on its membrane and
contains mitochondria, endoplasmic reticulum, and synaptic vesicles (SVs) in its cytoplasm. The membrane of SVs
has synaptotagmin and synaptobrevin proteins. SVs stores acetylcholine (ACh), the neurotransmitter at skeletal NMJ.
Each SV has around 5000-10000 molecules of Ach. The amount of neurotransmitter stored in each vesicle is
sometimes referred to as “quanta. The SVs are concentrated around the active zones, the areas of membrane
thickening at the nerve terminal that contains many proteins and rows of voltage-gated calcium (Ca) channels. The
nerve terminal membrane also contains a family of SNAP proteins; syntaxin and synaptosomal-associated protein 25
(SNAP-25) These proteins(syntaxin and SNAP-25) along with synaptic-vesicle protein synaptobrevin are referred to

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as SNARE (soluble N-ethylmaleimide-sensitive) proteins and are essential for docking and fusion of SVs to active
zones and resulting exocytosis of ACh in synaptic cleft. The space between the nerve terminal and the motor endplate
on the plasma membrane of muscle is called synaptic/junctional cleft and measures ∼50 nm. It is the site where
presynaptic neurotransmitters, ACh is released before it interacts with nicotinic ACh receptors on the motor endplate.
Synaptic cleft of NMJ contains acetylcholinesterase enzyme, responsible for the catabolism of released ACh so that
its effect on the post-synaptic receptors is not prolonged. Motor endplate forms the postsynaptic part of NMJ. It is the
thickened portion of the muscle plasma membrane (sarcolemma) that is folded to form depressions called junctional
folds. The nerve terminal does not penetrate the motor endplate but fits into the junctional folds. Junctional folds have
nicotinic ACh receptors concentrated at the top. Binding of ACh to these receptors opens the ion channels allowing
the influx of sodium ions from the extracellular fluid into the muscle membrane. This creates endplate potential and
generation and transmission of AP to muscle membrane.[2][3][5]

The neuromuscular junction of the smooth muscle is not highly structured as skeletal muscle NMJ. Smooth muscle
NMJ is formed between the autonomic nerve fibers that branch diffusely on smooth muscle to form diffuse junctions.
The autonomic nerve in smooth muscle NMJ does not have typical nerve terminals as seen in skeletal NMJ but
instead it has multiple varicosities distributed along its axis. Unlike skeletal NMJ that always has Ach as a
neurotransmitter, the SVs present in the varicosities may contain ACh or norepinephrine or another transmitter. The
Schwann cells are interrupted at the points where varicosities are present, so that neurotransmitter can diffuse to the
cells. The smooth muscles have many layers of muscle cells but the nerve fibers often innervate only the outer layer.
Muscle excitation travels from this outer layer to the inner layers by action potential conduction in the muscle mass or
by additional diffusion of the transmitter substance. In body parts where smooth muscle activity is relatively slow like
intestines, one neuron controls a large number of muscle fibers but parts where the activity is fast such as iris, the
autonomic nerve branch less extensively and controls fewer muscle fibers.[2][3]

Neuromuscular Junctions of Cardiac Muscle

Cardiac muscle fibers are connected by multiple gap junctions that provide a rapid spread of contraction within the
muscle. Each cardiac muscle fiber is innervated by postganglionic parasympathetic and sympathetic nerve endings,
which lose the myelin sheath closer to the individual muscle fiber; this allows free diffusion of the neurotransmitter
from the innervated nerve axon to the muscle fiber. The parasympathetic and sympathetic nerve fibers end on the
sinoatrial node, the atrioventricular node, and the bundle of His to form NMJ Sympathetic fibers also innervate the
ventricular muscle. The exact nature of the endings on nodal tissue is not known. In the ventricle, the contacts
between the sympathetic fibers and the cardiac muscle fibers resemble those found in smooth muscle.[1][2][3]

Organ Systems Involved

Any organ with neurological innervation is involved in neuromuscular transmission. That includes skeletal muscles,
smooth muscles, and cardiac muscles.[6]

Function
The nervous system can exert excitatory control over muscle contraction or can have an inhibitory influence on reflex
contractions and hyperreflexia. This control is achieved through the transfer of action potential from the nerve to the
target muscle with the help of a neurotransmitter so that nerve impulse can be converted appropriate muscle
contraction of the skeletal, smooth, or cardiac muscle. All vital functions that need voluntary or involuntary
contraction of skeletal, smooth or cardiac muscles such as circulation, respiration, digestion, urination, locomotion
etc. could be carried out efficiently due to intact NMJ and proper neuromuscular transmission.

Mechanism
When the nerve impulse from peripheral or central nervous system reaches the presynaptic membrane (nerve
terminal) of the neuromuscular junction in the form of the action potential, it triggers voltage-gated Ca2+ channels at
the active zones of nerve terminal to open, and Ca2+ ions enter the nerve terminal from the extracellular space.

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Increased intracellular calcium interact with SNARE proteins, this stimulates synaptic vesicles to fuse with active
zones and release of their content – ACh into the synaptic cleft. This process is named exocytosis. Increased
intracellular calcium in nerve terminals triggers the simultaneous release of a number of ACh quanta. The total
number of quanta of ACh released by a stimulated nerve markedly depends on the concentration of Ca2+ ions in the
extracellular fluid. If Ca2+ ions are not present, even electrical stimulation of the nerve, will not produce the release
of transmitter. A 2-fold increase in the extracellular calcium will cause a 16-fold increase in the quantal content of an
endplate potential.

Released ACh travels across the synaptic cleft towards the motor endplate and binds with the nicotinic ACh receptors,
triggering ACh-gated channels to open, and motor endplate on the muscle membrane becomes more permeable to
Na+ ions. This changes the membrane potential at the muscle membrane from -90 mV to -45 mV. This decrease in
membrane potential is called endplate potential. In the skeletal NMJ, the endplate potential is strong enough to
propagate action potential over the surface of the skeletal muscle membrane. This potential is carried along the
muscle fiber through the system of T tubules and triggers to release Ca2+ ions from the sarcoplasmic reticulum into
the sarcoplasm of muscle, which results in the construction of the muscle. The remaining ACh in the synaptic cleft
gets hydrolyzed by the enzyme acetylcholinesterase (AChE). Interestingly, the presynaptic part of NMJ, the nerve
terminal also has nicotinic ACh receptors. These receptors sense ACh in the synaptic cleft and, via a feedback system,
controls the release of ACh. If the concentration of ACh in the synaptic cleft has increased appropriately, the
presynaptic ACH receptors will sense and the nerve terminal will shut down more release. The difference between
pre- and postsynaptic ACh receptors is the response of these receptors to different ACh receptor agonists and
antagonist.[5][7]

Related Testing
Neuromuscular junction testing in skeletal muscle is done by a specific nerve conduction study called repetitive nerve
stimulation (RNS). Neuromuscular transmission failure during RNS is a trademark of NMJ diseases such as
Myasthenia Gravis (MG) and Lambert-Eaton syndrome (LES).

During RNS testing a sequence of supramaximal intensity impulses are applied to the nerve, and the response is
recorded from the corresponding muscle. Decrement or increment of response indicates a specific NMJ pathology. A
decremental response to RNS is seen in clinical muscle fatigue and weakness. Abnormal RNS is seen in more than
50% to 70% of generalized MG patients but in patients having only ocular MG, it is often normal. A 10% decrement
on slow RNS (2-3 Hz) is typically seen in patients with MG. In patients with ocular MG, electromyographic
abnormalities may be detectable only in facial muscles. It is important to maintain a skin temperature between 32ºC –
34ºC before beginning RNS because cold extremities may give false-negative results. If the skin is cold, there may be
reduced release of Ach with the first stimuli and this will leave more quanta for subsequent stimuli. In the LES,
repetitive nerve stimulation at high rates (30-50Hz) will cause considerable increments, usually exceeding 50-200%
of the baseline value. Botulism also shows an incremental response on fast RNS. Before conducting RNS testing, it is
recommended to at least test one motor and one sensory nerve in an upper and lower extremity first. The idea is to
rule out any other underlying cause that involves nerve or muscle such as peripheral neuropathy or motor neuron
disease.Needle EMG test is done utilizing singer fiber studies. These studies utilize a response called "jitter." Jitter is
usually a stable action but when unstable, suggests NMJ disorder is present.[8][9][8]

Detection of specific antibodies in patient's serum also aids the diagnosis of MG and LES . Both MG and LES are
autoimmune diseases. Around 85% of generalized MG and 50% of only ocular MG patients have ACh receptor
antibodies in their serum. For patients with ocular MG, who do not have ACh receptor antibodies in their serum, the
detection of muscle-specific kinase (MuSK) antibodies can be helpful in making the diagnosis.A positive serum
voltage-gated calcium channel antibody test and characteristic EMG findings may help diagnosis of LES[4].

Clinically, intravenous edrophonium is used to help make a diagnosis of MG. Edrophonium is a short-acting
cholinesterase inhibitor, its administration transiently improves weakness due to MG. Since edrophonium

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administration may lead to severe cholinergic reactions, including syncope, it is important to have atropine and proper
resuscitative facilities available before conducting this test.[4].

Pathophysiology
Myasthenia Gravis

Among the most common diseases of the skeletal neuromuscular junction is myasthenia gravis (MG). In over 60% of
cases, hyperplasia of the thymus gland is present when excessive T cells may predispose to an autoimmune response.
MG is an autoimmune disorder in which the body produces antibodies against its own ACh receptors in the
postsynaptic membrane. These antibodies bind to the ACh receptors and block the interaction of ACh with them
resulting in the blockage of NMJ transmission, muscle weakness, and paralysis. Acetylcholine receptor antibodies are
present in about 85% of patients with generalized symptoms but only 50% of patients with purely ocular involvement
MG characteristically presents with double vision (diplopia), drooping of the upper eyelids (ptosis), difficulty in
speaking (dysarthria), difficulty in swallowing (dysphagia) and general muscle fatigue. The symptoms are typically
least expressed in the morning and are worse in the evening as the amount of ACh bound to the postsynaptic
membrane receptor decreases due to various muscle activities during the day. In the progressive form of the disease,
the weakness may become steadily worse, may cause myasthenic crisis and death. Decrement of over 10% observed
following repetitive nerve stimulation is a diagnostic criterion for MG due to depletion of functional ACh in the
synaptic cleft.[6][4]

Muscle weakness can be temporarily relieved by ACh-esterase drugs such as physostigmine or neostigmine since they
increase the amount ACh in the synaptic cleft and enhance conduction through the NMJ. Corticosteroids and steroid-
sparing agents (azathioprine, cyclophosphamide, tacrolimus, or mycophenolate) are used to inhibit the immune
response in MG. Rituximab, an anti-CD20 B cell monoclonal antibody may be used in refractory patients, especially
with MuSK. Plasmapheresis is used to remove antibodies from the body. Plasmapheresis and IV immunoglobulins are
used to treat, complications of MG that include acute flare-ups of myasthenic crises and respiratory involvement.
Patients with a respiratory crisis may also require ventilatory support.[10]

Lambert Eaton Myasthenic Syndrome (LEMS) is another autoimmune disease affecting skeletal muscle NMJ when
the body produces antibodies against its own presynaptic membrane Ca2+ channels. Blocking Ca2+ channels in the
presynaptic membrane leads to less calcium entry into the nerve terminal and less ACh being released resulting in
weakness of skeletal muscles and fatigue that usually improves after physical activity. The exact cause of LEMS is
unknown but correlates with tumors of the lung, usually small cell lung cancer. The symptoms of LES are similar to
MG such as muscle weakness, and fatigue; however, what separates LES from MG is that in LES proximal limb
muscles are involved in the presence of depressed tendon re?exes a weakness improves with use. This is because with
repeated attempts at muscle contraction a calcium gradient builds up outside the presynaptic Ca channel, eventually
allowing the endogenous calcium to outcompete the auto-antibodies, to trigger the release of ACh in the synaptic
cleft. 80% of LES patients complain of proximal muscle weakness in both arms and legs. Oropharyngeal and ocular
muscles are mildly affected so, eyelid ptosis and mild diplopia may also be present. Autonomic symptoms such as dry
mouth, constipation, impotence in males and postural hypotension may be seen. The triad of proximal muscle
weakness, areflexia, and autonomic dysfunction aids in making the diagnosis. The increased response following
repetitive nerve stimulation is a diagnostic criterion for LEMS due to increased Ca2+ after supra-maximal
stimulation, resulting in increased functional ACh in the synaptic cleft.[4]

Botulism

Botulism is a potentially fatal syndrome of diffuse, flaccid paralysis caused by neurotoxins produced caused by
Clostridium botulinum, an anaerobic gram-positive, spore-forming bacterium. Of the several types of neurotoxins
produced by C. botulinum toxins B, D, F, and G selectively affect one or all of these SNARE proteins and block
docking, a fusion of SVs and exocytosis of Ach, resulting in muscle weakness or reversible flaccid paralysis.
Botulism can be foodborne. In adults, ingestion of food contaminated with spores or toxins (home-canned food) of
clostridium botulism result in nausea, vomiting, blurred vision, diplopia and descending ?accid paralysis. In severe
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cases bulbar paralysis and respiratory failure may occur rapidly. Infant botulism can occur due to ingestion of honey
contaminated with spores of C. botulism. Toxins are produced within the GI tract of infants and infants present with
constipation, weak feeding, weak crying and flaccid paralysis. History, clinical presentation and the detection of
botulinum toxin and the presence of C. botulinum in serum, stool, gastrointestinal content, or wound exudates form
the basis of diagnosis. Treatment is done by administering antitoxin. Early administration of antitoxin decreases
mortality and shortens the disease course. Patients may require prolonged periods of ventilation. Botulism can also
occur due to contamination of a wound with dust containing C. botulism spores. Such infection particularly common
after traumatic injuries and among drug abusers. Therapeutically, botulinum toxin is used to treat spasticity in
conditions such as blepharospasm, torticollis, anal sphincter spasm, etc. It is also used to treat axillary hyperhidrosis,
and cosmetically used to correct wrinkles.[4][18][11]

Clinical Significance
Various Drugs Affecting NMJ

There are few drugs like nicotine and carbamylcholine that mimic acetylcholine's action because of their similar
chemical structure. A direct agonist of ACh that directly binds to the ACh receptors includes bethanechol (which
treats post-operative ileus, urinary retention), carbachol, and pilocarpine (both used to treat glaucoma by constriction
of the pupillary muscle), and methacholine (challenge test to diagnose asthma in a patient who presents
asymptomatically).

NMJ blockers are used to induce muscle relaxation and paralysis. These can be divided into depolarizing
(succinylcholine) and non-depolarizing (tubocurarine, atracurium, mivacurium, pancuronium, vecuronium,
rocuronium). Drugs such as d-tubocurarine compete with ACh and bind to the ACh receptor on the postsynaptic
membrane, thus causing the skeletal muscle to relax instead of contraction after locally produced ACh. They are
called competitive blocking agents.

Drugs like succinylcholine also paralyze the skeletal muscle but through continued depolarization that prevents
repolarization of the motor endplate, resulting in ACh receptors becoming desensitized and inactivated. These drugs
are used in general anesthesia to help avoid large doses of general anesthetics. Administration of neuromuscular
blocking agents and drugs can also result in bulbar and respiratory muscle failure. ACh esterase inhibitors like
physostigmine neostigmine, pyridostigmine, and edrophonium increase the levels of ACh in the synaptic cleft.
Physostigmine and neostigmine are used for the treatment of Myasthenia Gravis (MG). Irreversible inhibitors of ACh
esterase includes the organophosphates commonly used as an insecticide, which includes malathion and parathion.
Exposure to these may cause organophosphate toxicity syndrome that includes diarrhea, urination, myosis,
bronchospasm, excessive lacrimation and salivation. The effects of irreversible inhibitors of ACh esterase can be
reversed by using a competitive inhibitor such as atropine and/or pralidoxime, which regenerates ACh esterase if
given early enough before enzyme aging occurs.[7][12]

Questions
To access free multiple choice questions on this topic, click here.

References
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[PubMed: 26439950]
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Lamont DJ, Simpson H, Simmen MW, Soeller C, Wishart TM, Gillingwater TH. Cellular and Molecular Anatomy
of the Human Neuromuscular Junction. Cell Rep. 2017 Nov 28;21(9):2348-2356. [PMC free article:
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4. Fagerlund MJ, Eriksson LI. Current concepts in neuromuscular transmission. Br J Anaesth. 2009 Jul;103(1):108-14.
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7. Martyn JA, Fagerlund MJ, Eriksson LI. Basic principles of neuromuscular transmission. Anaesthesia. 2009
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8. Rich MM. The control of neuromuscular transmission in health and disease. Neuroscientist. 2006 Apr;12(2):134-
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9. Howard JF. Electrodiagnosis of disorders of neuromuscular transmission. Phys Med Rehabil Clin N Am. 2013
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