Physiology, Neuromuscular Transmission


Article Author:
Sopiko Jimsheleishvili


Article Editor:
Andrew Sherman


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Jasleen Jhajj
Cliff Caudill
Evan Kaufman


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Carrie Smith
Abdul Waheed
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Kristina Soman-Faulkner
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Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
4/19/2019 8:32:48 PM

Introduction

The neuromuscular junction (NMJ) forms from a synaptic connection between the motor neuron and the skeletal muscle motor fiber. Acetylcholine (ACh) is the transmitter present in the NMJ of all skeletal muscles while synapses between neurons use a large number of various transmitters.

Cellular

Neuromuscular junctions in skeletal muscle form by nerve fibers derived from large alpha motor neurons located in the anterior gray horns of the spinal cord or the motor nuclei of cranial nerves in the brainstem. The spinal cord innervates the skeletal muscles of the body and extremities, while the brainstem provides motor control for skeletal muscles of the head and face. Axons from alpha motor neurons are myelinated until they reach the muscle fiber, where they lose their myelin sheath, branch extensively, and contact multiple muscle fibers. These branches end as a naked axon forming the neural element of the motor end-plate, from which the transmitter gets released. The plasma membrane of these axons forms a presynaptic membrane of the NMJ, which is separated from a postsynaptic membrane by a space about 50 to 100 nm wide.[1][2] The presynaptic membrane contains mitochondria, endoplasmic reticulum and many synaptic vesicles filled with the neurotransmitter. The postsynaptic membrane of the NMJ is within the muscle fiber. The space located between the presynaptic and postsynaptic terminals forms the synaptic cleft. The postsynaptic membrane is folded to increase surface area and contains many ACh receptors.[1][2][3]

Neuromuscular junctions in smooth muscle

Smooth muscle NMJ presynaptic terminals form by postganglionic non-myelinated axons from autonomic nerve fibers which branch extensively in the areas where the action is slow like in the smooth muscles of intestines, and a single neuron controls a large number of muscle fibers. In the longitudinal layers of intestinal smooth muscles, only a few muscles possess autonomic endings, and the contraction passes from one muscle fiber to another via gap junctions.

When fast action is necessary, for example in a smooth muscle of the iris, the autonomic nerve fibers branch less extensively, and a single neuron controls fewer muscle fibers.[2][3][4]

Neuromuscular junctions in 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 autonomic nerve endings, which become naked closer to the individual muscle fiber; this allows free diffusion of the neurotransmitter from the innervated nerve axon to the muscle fiber.[1][2][3]

Organ Systems Involved

Any organ with neurological innervation is involved in neuromuscular transmission. That includes skeletal muscles, visceral muscles, and cardiac muscles.

Function

The central nervous system interacts with skeletal muscle fibers via neuromuscular junctions in a few ways.  It can exert voluntary control over contraction. The CNS also acts as an inhibitory influence on reflex contractions and hyperreflexia. The primary function of the NMJ is to convert an action potential to a muscle contraction with the help of a neurotransmitter.

Mechanism

When an action potential reaches the presynaptic membrane of the neuromuscular junction, it triggers voltage-gated Ca2+ channels to open, and Ca2+ ions enter the axon terminal; this stimulates synaptic vesicles to fuse with the presynaptic membrane and release of their content – ACh into the synaptic cleft. This process is named exocytosis. Released ACh travels across the synaptic cleft towards the postsynaptic membrane and binds with the nicotinic type ACh receptors, triggering ACh-gated channels to open, and the postsynaptic membrane becomes more permeable to Na+ ions, allowing them to enter the muscle cells and create an action potential, called the end-plate potential. This potential is carried along the muscle fiber through the system of T tubules and triggers to release Ca2+ ions from the sarcoplasmic reticulum, which result in the construction of the muscle. The remaining ACh in the synaptic cleft gets hydrolyzed by the enzyme acetylcholinesterase (AChE).[4][5][6]

Related Testing

Neuromuscular junction testing in skeletal muscle is by a specific nerve conduction study called "repetitive nerve stimulation."  In this study, the examiner applies a sequence of impulses with supra-maximal intensity to the nerve, and the response recorded from the corresponding muscle. Decrement or increment of response indicates a specific NMJ pathology.  Exercise and post-exercise studies can bring out specific pathology.  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.

Pathophysiology

Various drugs affecting NMJ

There are few drugs like nicotine and carbamylcholine that mimic acetylcholine's action because of their similar chemical structure. Other 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 of the postsynaptic membrane. These drugs are used in general anesthesia to help avoid large doses of general anesthetics.[2][3][4]

Some foods in anaerobic conditions may contain a toxin produced from Clostridium botulinum, which inhibits ACh in the NMJ causing paralysis of the skeletal muscles including respiratory muscles that may result in death. Calcium gluconate enhances the release of ACh and may be used to alleviate symptoms.[7][8]

AChE inhibitors like physostigmine also increase the amount of ACh in the NMJ synapse and are used for the treatment of Myasthenia Gravis (MG). Other ACh-esterase inhibitors like organophosphates may cause organophosphate toxicity syndrome that includes diarrhea, urination, myosis, bronchospasm, excessive lacrimation and salivation.

Clinical Significance

Myasthenia Gravis

Among the most common diseases of the skeletal neuromuscular junction is myasthenia gravis (MG), which has an unknown cause. 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. 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.[9][10] 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.

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 are used to inhibit the immune response in MG. Plasmapheresis is used to remove antibodies from the body.[9][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 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 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.[11][12]


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Physiology, Neuromuscular Transmission - Questions

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A 29-year-old female presents to the outpatient clinic with complaints of drooping of the upper eyelids, double vision, difficulty in swallowing, general muscle weakness and fatigue. She reports that her symptoms started about a month ago and gradually worsened. She is fine in the morning when she wakes up but during the day she becomes weaker, and her symptoms worsen in the evening. What will the most sensitive diagnostic test show for this condition?



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While making breakfast in the morning, a man touches the handle of a cooking pan that ends up being very hot. He quickly removes his hand from the handle to prevent burning it. Which ion triggers the release of the neurotransmitter that results in this quick muscle contraction?



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A 65-year-old male who is also a smoker presents to the clinic after he was found to have an increment on repetitive nerve stimulation test. His main complaint is weakness and fatigue. Which disease causes the syndrome associated with his muscle weakness?



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An anesthetist is preparing a 75-year-old male patient for lumbar spine surgery. He uses a particular medication to relax the patient’s muscles prior to intubation. How does the mechanism of action of this medication differ from the mechanism of action of acetylcholine competitive inhibitors?



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A 33-year-old woman attended a party. Forty-eight hours later, she woke up in the middle of the night with severe nausea, which was quickly followed by vomiting and diarrhea. By morning, she noticed that she had sagging of her upper eyelids and difficulty in moving her eyes. Later during the day she experienced weakness of the jaw muscles and had difficulty in swallowing (dysphagia). Two friends who had also attended the party also had similar symptoms. What is the mechanism of action of the protein that is involved in this condition?



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Physiology, Neuromuscular Transmission - References

References

Slater CR, The Structure of Human Neuromuscular Junctions: Some Unanswered Molecular Questions. International journal of molecular sciences. 2017 Oct 19;     [PubMed]
Slater CR, The functional organization of motor nerve terminals. Progress in neurobiology. 2015 Nov;     [PubMed]
Jones RA,Harrison C,Eaton SL,Llavero Hurtado M,Graham LC,Alkhammash L,Oladiran OA,Gale A,Lamont DJ,Simpson H,Simmen MW,Soeller C,Wishart TM,Gillingwater TH, Cellular and Molecular Anatomy of the Human Neuromuscular Junction. Cell reports. 2017 Nov 28;     [PubMed]
Brown MC,Holland RL,Hopkins WG, Motor nerve sprouting. Annual review of neuroscience. 1981;     [PubMed]
Tintignac LA,Brenner HR,Rüegg MA, Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting. Physiological reviews. 2015 Jul;     [PubMed]
Sanes JR,Lichtman JW, Development of the vertebrate neuromuscular junction. Annual review of neuroscience. 1999;     [PubMed]
Meunier FA,Schiavo G,Molgó J, Botulinum neurotoxins: from paralysis to recovery of functional neuromuscular transmission. Journal of physiology, Paris. 2002 Jan-Mar;     [PubMed]
Rogozhin AA,Pang KK,Bukharaeva E,Young C,Slater CR, Recovery of mouse neuromuscular junctions from single and repeated injections of botulinum neurotoxin A. The Journal of physiology. 2008 Jul 1;     [PubMed]
Phillips WD,Vincent A, Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Research. 2016;     [PubMed]
Plomp JJ,Huijbers MGM,Verschuuren JJGM, Neuromuscular synapse electrophysiology in myasthenia gravis animal models. Annals of the New York Academy of Sciences. 2018 Jan;     [PubMed]
Fukuoka T,Engel AG,Lang B,Newsom-Davis J,Prior C,Wray DW, Lambert-Eaton myasthenic syndrome: I. Early morphological effects of IgG on the presynaptic membrane active zones. Annals of neurology. 1987 Aug;     [PubMed]
Vincent A,Lang B,Newsom-Davis J, Autoimmunity to the voltage-gated calcium channel underlies the Lambert-Eaton myasthenic syndrome, a paraneoplastic disorder. Trends in neurosciences. 1989 Dec;     [PubMed]

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