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Structure and function of neuromuscular junction, centered on muscle‐specific tyrosine kinase and related proteins
Author(s) -
Takamori Masaharu
Publication year - 2016
Publication title -
clinical and experimental neuroimmunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.297
H-Index - 15
ISSN - 1759-1961
DOI - 10.1111/cen3.12314
Subject(s) - agrin , neuromuscular junction , microbiology and biotechnology , postsynaptic potential , postsynaptic density , acetylcholine receptor , chemistry , neuroscience , biology , biochemistry , receptor
Muscle‐specific tyrosine kinase (Mu SK ) is uniquely positioned as a key protein in the neuromuscular junction, particularly in relation to acetylcholine receptor ( AC hR) clustering in the postsynaptic membrane, and pre‐ and postsynaptic differentiations. The present review focuses on the functional mechanisms in the neuromuscular junction structures centered on Mu SK and related proteins. (i) The Wnt non‐canonical pathway through the Wnt/Mu SK cysteine‐rich domain (coreceptor: low‐density lipoprotein receptor‐related protein 4 [Lrp4])/Dishevelled (scaffolding protein) signaling; this localizes aneural microclusters of AC hR at the central part of the postsynaptic membrane in parallel with axonal guidance, and converges on the neural agrin/Lrp4/Mu SK immunoglobulin‐like domains 1 and 2 (Ig 1/2 domains) pathway to form innervated full‐sized AC hR clusters. (ii) The presynaptic homeostasis (upregulation of acetylcholine release) compensates postsynaptic impairments by the fast‐mode of endocytosis in the nerve terminal and the trans‐synaptic retrograde signals including Wnt‐Mu SK cysteine‐rich domain canonical pathway (including β‐catenin), Lrp4 and laminin β2. (iii) The extracellular matrix contributive to the neuromuscular junction formation and maintenance includes collagen Q, perlecan, biglycan and dystroglycans; collagen Q and biglycan link to Mu SK (first and second immunoglobulin‐like domains and cysteine‐rich domain) and acetylcholinesterase on one hand and to the intracellular cytoskeleton through dystroglycans on the other hand, so that Mu SK participates in not only AC hR clustering at the muscle surface and acetylcholinesterase‐controlled muscle membrane sensitivity to acetylcholine, but also the postsynaptic stability reinforced by cytoskeletal dynamics; the laminin network including muscle agrin also contributes to synaptic stability through dystroglycans; the agrin‐enhanced phosphorylation of cortactin promotes cytoskeletal dynamics to stabilize AC hR clusters; the interaction of neuregulin 1 with the receptor tyrosine kinase of EGF receptor family (ErbB receptor) contributes to the postsynaptic stabilization and also Mu SK phosphorylation leading to AC hR clustering. (iv) The muscle contractile mechanisms are controlled by release and restoration of the sarcoplasmic Ca 2+ being mediated through the receptor and channel proteins. Insight into these fine structures will foster further immunological approaches to search for new antigenic targets and to enhance antibody detection in myasthenia gravis.