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. 2020 May 28;13:86. doi: 10.3389/fnmol.2020.00086

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Copyright © 2020 Takamori.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Functional organization for synaptic transmission in neuromuscular junction (NMJ) and antibody-targets. (A) Presentation by staining of cultured rat myotube with fluorescence-labeled α-bungarotoxin and by the image analyzing using a laser cytometer, indicating acetylcholine receptor (AChR) cluster (red), a synaptic stabilizing organization including extracellular matrix proteins (gree and light blue). The image is constructed on ACAS 570 (Meridian Instruments Inc., Okemos, MI, USA) which provides a graded pseudocolor image on the computer display. (B) Schematic presentation of the post-synaptic structures. Y marks attached with numbers indicate the antibodies to recognize respective targets of the functional structures. Gray frame indicates the acetylcholine receptor (AChR) cluster formation. Pink frames indicate AChR clustering by way of two signaling pathways mediated via the muscle-specific tyrosine kinase (MuSK) 1/2 domains (green-limit in the pink MuSK ectodomain and green line with arrowhead) and MuSK cysteine-rich domain (CRD; red-limit in the pink MuSK ectodomain and red-line with arrowhead), the signals of which are mediated by Dishevelled (Dvl, adaptor protein). The low-density lipoprotein receptor-related protein 4 (Lrp4) is the receptor for agrin (partly for Wnts as described in the text). The small GTPases (shown in the pink frame of Kinases) effector PAK1 (p21-activated kinase 1) acts as a bridging molecule between the Wnt- and agrin-signaling pathways. From “inside” the muscle cell, MuSK is activated by Dok7 (downstream kinase); Dok7 recruits two adaptor protein, Crk and Crk-L (CT10 regulators of kinase) for rapsyn-anchored AChR cluster formation. The formed AChR clusters are anchored at the endplate membrane by rapsyn and immobilized by MuSK-linking heat-shock proteins (HSPs): tumorous imaginal disc 1 short form (Tid1s), HSP 70 and HSP 90β. Tid1s is required for the MuSK-Dok7 signaling during the MuSK activation. The interaction of neuregulin 1 (NRG 1) with ErbB receptor (receptor tyrosine kinase of epidermal growth factor receptor family) increases the MuSK tyrosine phosphorylation (via Erbin) and thereby modulates the MuSK-dependent AChR clustering. Caveolin 3 binds with the MuSK kinase domain and thereby driving AChR clustering. Yellow frames indicate the organizations for synaptic stability and maintenance. The synaptic stability of NMJ including AChR clusters (gray frame), MuSK (pink frame), Lrp4 (pink frame) and acetylcholinesterase (AChE) is modulated by extracellular matrix proteins (collagen Q, perlecan, biglycan, laminin-network including muscle agrin and laminins and dystroglycan) worked in cooperation with the cytoskeleton. The interaction of NRG 1 (neuregulin 1) with ErbB receptor (pink frames) contributes to the cytoskeletal organization through α-dystrobrevin phosphorylation on one hand (yellow frame) and the MuSK activation via Erbin on the other hand (pink frame). The downstream effector of Dok7-recruited Crk-L (Sorbs1/2) acts on the cytoskeleton for synaptic stability. Collagen Q-Perlecan and Biglycan act on Dystroglycans in cooperation with cytoskeleton for synaptic stability on one hand (yellow frame) and implicate in AChR cluster formation via their interaction with pink-MuSK ectodomains (Ig1 shown by green limit with a green line and CRD shown by red limit with red line) on the other hand. The former is cooperated by linking to dystrophin/utrophin-associated protein complex; the latter is cooperated by linking with rapsyn to firmly anchor AChR clusters at the post-synaptic membrane. Cortactin (yellow frame) has the function of phosphorylation-dependent signaling downstream from Agrin/Lrp4/MuSK (pink frame) in promoting actin polymerization and also stabilizing AChR clusters at the postsynaptic membrane. Coronin 6 is the actin-binding protein contributive to synaptic stability. Targets recognized by antibodies: Y1, Acetylcholine receptor (AChR); Y2, Muscle-specific tyrosine kinase (MuSK) 1/2 domains; Y3, MuSK cysteine-rich domain (CRD); Y4, Low-density lipoprotein receptor-related protein 4 (Lrp4); Y5, neural Agrin; Y6, Collagen Q; Y7, Cortactin.