Neuromuscular junction
681908
224122553
2008-07-07T12:20:23Z
Arcadian
104523
split out [[Neuromuscular junction disease]]
[[Image:NMJ.jpg|thumb|300px|[[Electron microscope|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: [http://www.nimh.nih.gov/Neuroinformatics/shins04.cfm NIMH] ]]
A '''neuromuscular junction''' ('''NMJ''') is the [[synapse]] or junction of the [[axon]] terminal of a [[motoneuron]] with the '''motor end plate''', the highly-excitable region of [[muscle|muscle fiber]] [[plasma membrane]] responsible for initiation of [[action potential]]s across the muscle's surface, ultimately causing the muscle to contract. In vertebrates, the signal passes through the neuromuscular junction via the [[neurotransmitter]] [[acetylcholine]].
==Anatomy==
[[Image:Synapse diag3.png|thumb|300px|Global view of a neuromuscular junction:<BR>1. [[Axon]]<BR>2. Motor end-plate<BR>3. [[Muscle fiber]]<BR>4. [[Myofibril]]]] Motor neuron ([[efferent]]) axons originating in the [[spinal cord]] enter muscle fibers, where they split into many [[myelin sheath|unmyelinated]] branches. These terminal fibers run along the myocytes to end at the neuromuscular junction, which occupies a depression in the [[sarcolemma]]. Each motor neuron can innervate from one to over 25,000 <ref>{{cite book | author = Dale Purves (Editor), George J. Augustine (Editor), David Fitzpatrick (Editor), William C. Hall (Editor), Anthony-Samuel Lamantia (Editor), James O. McNamara (Editor), S. Mark Williams (Editor) | title = Neurosciences | edition = 3 | translation = french | pages = 377 | year = 2005 | isbn = 978-0878937257}}</ref> muscle fibers, but muscle fiber receives inputs from only one motor neuron.
In the [[Chemical synapse#Anatomy and physiology|terminal bouton]] of the motor nerve, structures known as presynaptic active zones accumulate [[synaptic vesicle]]s filled with the neurotransmitter acetylcholine.
On the muscle side of the junction, the muscle fiber is folded into grooves called prejunctional folds that mirror the postsynaptic active zones, the spaces between the folds contain the enzyme acetylcholinesterase.
The muscle surface is covered by the synaptic [[basal lamina]]. Postjunctional folds are characteristic of skeletal muscle, particularly in fast muscle fibers.
==Mechanism of action==
[[Image:Synapse diag4.png|thumb|300px|Detailed view of a neuromuscular junction:<BR>1. [[Presynaptic]] terminal<BR>2. [[Sarcolemma]]<BR>3. [[Synaptic vesicle]]<BR>4. [[Nicotinic acetylcholine receptor]]<BR>5. [[Mitochondrion]]]]
Upon the arrival of an [[action potential]] at the axon terminal, [[voltage-dependent calcium channel]]s open and Ca<sup>2+</sup> [[ions]] flow from the [[extracellular fluid]] into the motor neuron's [[cytosol]]. This influx of Ca<sup>2+</sup> triggers a biochemical cascade that causes [[neurotransmitter]]-containing [[Synaptic vesicle|vesicles]] to fuse to the motor neuron's [[cell membrane]] and release acetylcholine into the [[synapse|synaptic cleft]], a process known as [[exocytosis]].
Acetylcholine diffuses across the synaptic cleft and binds to the [[nicotinic acetylcholine receptor]]s that dot the motor end plate.
The receptors are [[ligand-gated ion channel]]s, and when bound by acetylcholine, they open, allowing sodium and potassium ions to flow in and out of the muscle's cytosol, respectively.
Because of the differences in [[electrochemistry|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 into [[muscle|transverse tubules]], eliciting the release of calcium from the [[sarcoplasmic reticulum]], thus initiating muscle contraction.
The action of acetylcholine is terminated when the [[enzyme]] [[acetylcholinesterase]] degrades the neurotransmitter and the unhydrolysed neurotransmitter diffuses away.
==Development of the neuromuscular junction==
The formation of the neuromuscular junction during embryonic development is well understood.
During development, the [[Growth cone|growing end]] of [[motor neuron]] axons secrete a [[protein]] known as '''[[agrin]]'''.
This protein binds to several [[receptor (biochemistry)|receptor]]s on the surface of skeletal muscle.
The receptor which seems to be required for formation of the neuromuscular junction is called the '''[[MuSK protein]]''' (Muscle specific kinase).<ref>{{cite journal | author = 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 | title = The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo | journal = Cell | volume = 85 | issue = 4 | pages = 501–12 | year = 1996 | pmid = 8653786 | doi = 10.1016/S0092-8674(00)81251-9}}</ref>
MuSK is a receptor [[tyrosine kinase]] - meaning that it induces cellular signaling by causing the release of [[phosphate]] molecules to particular [[tyrosine]]s on itself, and on proteins which bind the [[cytoplasm]]ic [[protein domain|domain]] of the receptor.<ref>{{cite journal | author = Valenzuela D, Stitt T, DiStefano P, Rojas E, Mattsson K, Compton D, Nuñez L, Park J, Stark J, Gies D | title = Receptor tyrosine sinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury | journal = Neuron | volume = 15 | issue = 3 | pages = 573–84 | year = 1995 | pmid = 7546737 | doi = 10.1016/0896-6273(95)90146-9}}</ref>
Upon activation by its ligand agrin, MuSK signals via two proteins called "[[Dok-7]]" and "[[rapsyn]]", to induce "clustering" of [[acetylcholine]] receptors (AChR).<ref> {{cite journal | author = 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 | title = Agrin acts via a MuSK receptor complex | journal = Cell | volume = 85 | issue = 4 | pages = 513–23 | year = 1996 | pmid = 8653787 | doi = 10.1016/S0092-8674(00)81252-0}}</ref>
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 "[[transgenic|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.<ref>{{cite journal | author = 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 | title = The muscle protein Dok-7 is essential for neuromuscular synaptogenesis | journal = Science | volume = 312 | issue = 5781 | pages = 1802–5 | year = 2006 | pmid = 16794080 | doi = 10.1126/science.1127142}} [http://www.sciencemag.org/cgi/content/abstract/312/5781/1802 link]</ref>
Many other proteins also comprise the NMJ, and are required to maintain its integrity.<ref>{{cite journal | author = Strochlic L, Cartaud A, Cartaud J | title = The synaptic muscle-specific kinase (MuSK) complex: new partners, new functions | journal = Bioessays | volume = 27 | issue = 11 | pages = 1129–35 | year = 2005 | pmid = 16237673 | doi = 10.1002/bies.20305}}</ref>
==See also==
* [[Synapse]]
* [[Skeletal muscle]]
* [[Nicotinic acetylcholine receptor]]
* [[Neuromuscular blocking drugs]]
* [[Neuromuscular junction disease]]
==External links==
* {{BUHistology|21501lca}}
==Further reading==
* {{cite book|last=Kandel|first=ER|coauthors=Schwartz JH, Jessell TM.|authorlink=Eric R. Kandel|title=[[Principles of Neural Science]]|edition=4th ed.|publisher=McGraw-Hill|location=New York|year=2000|isbn=0-8385-7701-6|series=}}
* {{cite book|last=Nicholls|first=J.G.|coauthors=A.R. Martin, B.G. Wallace and P.A. Fuchs|title=From Neuron to Brain|edition=4th ed.|publisher=Sinauer Associates|location=Sunderland, MA.|year=2001|isbn=0878934391|series=}}
* {{cite book|last=Engel|first=A.G.|title=Myology|edition=3rd ed.|publisher=McGraw Hill Professional|location=New York|year=2004|isbn=0-07-137180-X|series=}}
==References==
<references/>
{{Nervous tissue}}
[[Category:Somatic motor system]]
[[Category:Skeletal muscle]]
[[Category:Neurophysiology]]
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[[pt:Junção neuromuscular]]
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