Neuromuscular junction
Oxford Companion to the Body:
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neuromuscular junction
The body contains over 600 different skeletal muscles and each consists of thousands of muscle fibres ranging in length from a few millimetres to several centimetres. The motor nerve fibres innervating them, which arise in the spinal cord, can be more than 1 m in length. However, the area of apposition between the terminal tip of each nerve fibre and the ‘endplate’ of each muscle fibre is usually less than 50 μm (1/20 mm) in diameter. This particular type of synapse is called the neuromuscular junction (see figure). In order to generate the complex and finely controlled movements that we all take for granted, there has to be a very efficient, fail-safe, and one-way transmission between the nerve and the muscle that ensures that muscle contractions faithfully follow commands from the central nervous system. Such neuromuscular transmission depends on the release from the motor nerve terminal of the chemical acetylcholine (ACh), and its binding to a protein receiver on the surface of the muscle, called the acetylcholine receptor (AChR).
When a nerve impulse reaches the motor nerve terminal, specialized proteins forming ion-channels in its cell membrane open transiently, allowing a short-lived entry of calcium into the terminal. Stored inside the nerve terminal, and attached to special sites on the inside of the cell membrane, are small round vesicles filled with ACh. The sudden inrush of calcium causes some of the vesicle membranes to fuse with the nerve terminal membrane, and to release their contents into the synaptic cleft between the nerve and the surface of the muscle fibre (see figure (d) ).
ACh diffuses rapidly across the ultramicroscopic 50 nm gap and binds to the AChRs that are very densely packed on the tops of the synaptic folds on the muscle fibre (see figure (c), (d) ). When two ACh molecules bind to each AChR, its central pore (channel) opens, allowing small positively charged ions, mainly sodium, to enter the muscle, resulting in a local reduction in the potential across the membrane (depolarization). The release of many ACh-containing vehicles by a nerve impulse leads to a large depolarization called the endplate potential, which in turn opens the voltage-sensitive sodium channels situated at the base of each synaptic fold (see figure (d) ). These are responsible for starting an ‘all or nothing’ action potential that is propagated along the muscle fibre in each direction and initiates muscle contraction.
After about a millisecond, the AChR pore closes and ACh unbinds and is broken down by an enzyme, ACh esterase (AChE), that sits in the synaptic cleft (see figure (d) ). Choline is then taken back into the nerve terminal by special transporters, and used to make more ACh; this is stored in newly-formed synaptic vesicles, themselves made up of recycled nerve terminal membrane. The whole sequence of events, from the inrush of calcium to the initiation of the action potential, takes place in less than two milliseconds.
Many of the earliest studies on chemical synaptic transmission began with the autonomic nervous system, but they were soon extended to skeletal muscles when Dale and his colleagues (1936) showed that stimulation of motor nerves released ACh, and that ACh can induce muscle contraction. The action of ACh could be increased by using a drug, eserine, that inhibits the ACh esterase, and the action of ACh on the muscle could be blocked by the arrow poison, curare. Katz and his co-workers subsequently used intracellular micro-electrodes to measure the endplate potentials and showed that these followed the release of many vesicles of ACh, and that a similar depolarization of the muscle occurred when ACh was applied directly onto the neuromuscular junction with a micropipette.
(a) A silver-stained nerve trunk and three myelinated nerves synapsing on the surface of the muscle. Each myelinated nerve ends as a series of fine, unmyelinated terminals that spread out over the neuromuscular junction. (b) An electron micrograph of a single nerve terminal and the adjacent muscle fibre. There are many mitochondria in both the nerve and the muscle. The surface of the muscle fibre apposed to the nerve terminal is thrown into a series of folds. (c) A higher magnification of part of (b). The nerve terminal contains many synaptic vesicles. At the top of the muscle folds the membrane is strongly stained because of the high density of AChRs. Just beneath the folds the muscle fibrils, which are responsible for muscle contraction, can be seen in cross-section. (d) A diagram depicting the main components of neuromuscular transmission and their roles (see text). (a), (b), and (c) courtesy of Dr Clarke Slater, University of Newcastle
(Click to enlarge)
The neuromuscular junction, unlike most of the nervous system, is accessible to factors circulating in the blood. This can be both an advantage and a disadvantage. For many surgical operations, one of the important roles of the anesthetist is to relax the patient's muscles using an intravenous injection of the otherwise poisonous curare-like drugs — whilst taking over artificially the muscular function of breathing. Similarly, many species of venomous animals, such as snakes and scorpions, make toxins that paralyse their prey, and in some parts of the world this can also be a serious hazard for humans. Such toxins are rapidly absorbed and carried to the neuromuscular junction where they bind with extraordinary efficiency to the AChRs and other ion channel proteins, leading to muscle paralysis which can prevent breathing. Another important toxin is botulinum, which is produced by bacteria contaminating certain foods. Botulinum toxin blocks the release of ACh from the motor nerve terminals, and can cause fatal paralysis in babies; on the other hand it has recently found use as a treatment by local injection into muscles that are subject to uncontrollable severe spasm.
These neurotoxins have also provided marvellous tools for investigating function. For instance, a particular snake toxin, alpha-bungarotoxin, binds very strongly to AChRs and has been of immense use in the study of diseases that affect neuromuscular transmission. In myasthenia gravis (mys: muscle: aesthenia: weakness), the patient suffers from serious weakness and fatigue that can be life-threatening if it involves swallowing and breathing muscles. Myasthenia was first described in 1672 by the very distinguished London physician and anatomist, Thomas Willis. Over three hundred years later, Jim Patrick and Jon Lindstrom at the Salk Institute in California induced a myasthenia gravis-like disease in rabbits by injecting them with AChR protein purified from the electric organs of certain fish. The rabbits responded to the ‘foreign’ protein by making antibodies to it, but these antibodies gained access to the rabbits' neuromuscular junctions, recognized the muscle AChRs, and reduced their function, producing muscle weakness. Following these experimental observations, radioactively-labelled alpha-bungarotoxin was used to show that patients with myasthenia have reduced numbers of AChRs at their neuromuscular junctions, and subsequently that this is caused by serum antibodies that bind to AChRs — just as in the rabbits. Drugs that inhibit the ACh esterase enzyme cause clinical improvement because they prolong the action of ACh, as first demonstrated in 1934 by Mary Walker, a young doctor in London, but nowadays the most important treatment is to reduce the circulating antibodies that bind AChR.
— Angela Vincent
Bibliography
- Hughes, J. T. (1991). Thomas Willis 1621-1675. His life and work. Royal Society of Medicine Services Ltd., London.
- Katz, B. (1966). Nerve muscle and synapse. McGraw Hill, Inc., New York.
- Vincent, A. and Wray, D. (1992). Neuromuscular transmission: basic and applied aspects. Pergammon Press, Oxford
See also skeletal muscle; synapse.
Oxford Dictionary of Sports Science & Medicine:
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neuromuscular junction
The site at which a motor neurone meets and communicates with a muscle fibre. At the junction, a small gap (the synaptic cleft) separates the neurone from the muscle fibre. This gap is bridged by the release of a neurotransmitter, such as acetylcholine.
Oxford Dictionary of Biochemistry:
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neuromuscular junction
the place of contact between the motor end-plate of the fibre of a motor neuron and the membrane of a muscle fibre supplied by the neuron. Impulses are transmitted across the gap by diffusion of a neurotransmitter. Compare synapse.
| neuromuscular, neuromodulator, neuromedin N | |
| neuron, neuronatin, neuropeptide |
Mosby's Dental Dictionary:
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neuromuscular junction
n
The area of contact between the ends of a large myelinated nerve fiber and a fiber of skeletal muscle. Also called myoneural junction.
Wikipedia on Answers.com:
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Neuromuscular junction
| Neuromuscular junction | |
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| Electron micrograph showing a cross section through the neuromuscular junction. T is the axon terminal, M is the muscle fiber. The arrow shows junctional folds with basal lamina. Postsynaptic densities are visible on the tips between the folds. Scale is 0.3 µm. Source: NIMH | |
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| Detailed view of a neuromuscular junction: 1. Presynaptic terminal 2. Sarcolemma 3. Synaptic vesicle 4. Nicotinic acetylcholine receptor 5. Mitochondrion |
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| Latin | synapsis neuromuscularis; junctio neuromuscularis |
| Code | TH H2.00.06.1.02001 |
A neuromuscular junction (NMJ) is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract. In vertebrates, the signal passes through the neuromuscular junction via the neurotransmitter acetylcholine.
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Contents
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Mechanism of action
See also: Excitation-contraction coupling
The neuromuscular junction is the location where the neuron activates muscle to contract. This is a step in the excitation-contraction coupling of skeletal muscle.
- Upon the arrival of an action potential at the presynaptic neuron terminal, voltage-dependent calcium channels open and Ca2+ ions flow from the extracellular fluid into the presynaptic neuron's cytosol.
- This influx of Ca2+ causes neurotransmitter-containing vesicles to dock and fuse to the presynaptic neuron's cell membrane through SNARE proteins.
- Fusion of the vesicular membrane with the presynaptic cell membrane results in the emptying of the vesicle's contents (acetylcholine) into the synaptic cleft, a process known as exocytosis.
- Acetylcholine diffuses into the synaptic cleft and binds to the nicotinic acetylcholine receptors bound to the motor end plate.
- These receptors are ligand-gated ion channels, and when they bind acetylcholine, they open, allowing sodium ions to flow in and potassium ions to flow out of the muscle's cytosol.
- Because of the differences in electrochemical gradients across the plasma membrane, more sodium moves in than potassium out, producing a local depolarization of the motor end plate known as an end-plate potential (EPP).
- This depolarization spreads across the surface of the muscle fiber and continues the excitation-contraction coupling to contract the muscle.
- The action of acetylcholine is terminated when the enzyme acetylcholinesterase degrades part of the neurotransmitter (producing choline and an acetate group) and the rest of it diffuses away.
- The choline produced by the action of acetylcholinesterase is recycled — it is transported, through reuptake, back into the presynaptic terminal, where it is used to synthesize new acetylcholine molecules.[1]
Acetylcholine is a neurotransmitter synthesized in the human body from dietary choline and acetyl-CoA (ACoA). One of the first neurotransmitters discovered, the substance was originally referred to as "vagusstoff" because it was found to be released by the stimulation of the vagus nerve. Later, it was established that acetylcholine is, in fact, important in the stimulation of all muscle tissue and that its action may be either excitatory or inhibitory, depending on a number of factors. Within the body, the synaptic action of acetylcholine usually quickly comes to a halt, the neurotransmitter naturally breaking down soon after its release. However, some nerve gases are designed to thwart this breakdown, causing prolonged stimulation of the receptor cells and resulting in severe muscle spasms.
Development of the neuromuscular junction
The complex series of steps leading to the formation of the neuromuscular junction during embryonic development are only partially understood.
During development, the growing end of motor neuron axons secrete a protein known as agrin.
This protein binds to several receptors on the surface of skeletal muscle.
The receptor which seems to be required for formation of the neuromuscular junction is the MuSK protein (Muscle specific kinase).[2]
MuSK is a receptor tyrosine kinase - meaning that it induces cellular signaling by causing the release of phosphate molecules to particular tyrosines on itself, and on proteins which bind the cytoplasmic domain of the receptor.[3]
Upon activation by its ligand agrin, MuSK signals via two proteins called "Dok-7" and "rapsyn", to induce "clustering" of acetylcholine receptors (AChR).[4]
In addition to the AChR and MuSK, other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the NMJ.
Knockout studies
These findings were demonstrated in part by mouse "knockout" studies. In mice which are deficient for either agrin or MuSK, the neuromuscular junction does not form. Further, mice deficient in Dok-7 did not form either acetylcholine receptor clusters or neuromuscular synapses.[5]
Many other proteins also comprise the NMJ, and are required to maintain its integrity.[6]
Neuromuscular block
Further information: Neuromuscular junction disease and Neuromuscular blocking drugs
A block or decrease in the transmission across the neuromuscular junction can cause a complete or relative loss of muscle function. It can result from neuromuscular junction diseases or be intentionally induced with neuromuscular blocking drugs. It can also be a side effect of other drugs that are generally not classified as neuromuscular blocking drugs, such as some anesthetic drugs.[7]
The degree of neuromuscular block may be estimated by Bromage score, which originally had four grades designate with the Roman numerals I until IV, but later complemented by Breen et al. with an inverse grading with Hindu-Arabic numerals:[7]
| Bromage score[7] | |||
|---|---|---|---|
| Grade | Criteria | Approximate degree of block |
|
| IV | 1 | Complete block, inability to move feet or knees | 100% |
| III | 2 | Almost complete block, ability to move feet only, with inability to flex knees | 66% |
| II | 3 | Partial block, ability to flex knees | 33% |
| 4 | Detectable weakness of hip flexion while supine, ability of full flexion of knees | ||
| 5 | No detectable weakness of hip flexion while supine | ||
| I | 6 | Free movement of legs and feet, ability to perform partial knee bend | 0% |
In unconscious patients, such as during anesthesia, neural block can be assessed by a "train-of-four" by stimulating muscles from surface electrodes.
See also
External links
Further reading
- Kandel, ER; Schwartz JH, Jessell TM. (2000). Principles of Neural Science (4th ed.). New York: McGraw-Hill. ISBN 0-8385-7701-6.
- Nicholls, J.G.; A.R. Martin, B.G. Wallace and P.A. Fuchs (2001). From Neuron to Brain (4th ed.). Sunderland, MA.: Sinauer Associates. ISBN 0-87893-439-1.
- Engel, A.G. (2004). Myology (3rd ed.). New York: McGraw Hill Professional. ISBN 0-07-137180-X.
References
- ^ Dale Purves, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White (2008). Neuroscience. 4th ed.. Sinauer Associates. pp. 121–2. ISBN 978-0-87893-697-7.
- ^ DeChiara T, Bowen D, Valenzuela D, Simmons M, Poueymirou W, Thomas S, Kinetz E, Compton D, Rojas E, Park J, Smith C, DiStefano P, Glass D, Burden S, Yancopoulos G (1996). "The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo". Cell 85 (4): 501–12. doi:10.1016/S0092-8674(00)81251-9. PMID 8653786.
- ^ Valenzuela D, Stitt T, DiStefano P, Rojas E, Mattsson K, Compton D, Nuñez L, Park J, Stark J, Gies D (1995). "Receptor tyrosine sinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury". Neuron 15 (3): 573–84. doi:10.1016/0896-6273(95)90146-9. PMID 7546737.
- ^ Glass D, Bowen D, Stitt T, Radziejewski C, Bruno J, Ryan T, Gies D, Shah S, Mattsson K, Burden S, DiStefano P, Valenzuela D, DeChiara T, Yancopoulos G (1996). "Agrin acts via a MuSK receptor complex". Cell 85 (4): 513–23. doi:10.1016/S0092-8674(00)81252-0. PMID 8653787.
- ^ Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, Akiyama T, Iwakura Y, Higuchi O, Yamanashi Y (2006). "The muscle protein Dok-7 is essential for neuromuscular synaptogenesis". Science 312 (5781): 1802–5. doi:10.1126/science.1127142. PMID 16794080. link
- ^ Strochlic L, Cartaud A, Cartaud J (2005). "The synaptic muscle-specific kinase (MuSK) complex: new partners, new functions". Bioessays 27 (11): 1129–35. doi:10.1002/bies.20305. PMID 16237673.
- ^ a b c AnaesthesiaUK > Bromage scale Created: 30/11/2004
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