The involvement of calcineurin in acetylcholine receptor redistribution in muscle.
In this study the intracellular signaling involved in acetylcholine receptor (AChR) redistribution in muscle was investigated. In cultured Xenopus embryonic muscle cells, both the dispersal of preexisting AChR clusters and the induction of new AChR clusters by growth factor-coated polystyrene beads were inhibited by two specific antagonists of the ser/thr phosphatase calcineurin (CaN), Cyclosporin A, (CsA) and FK-506, but not by KN-93 that blocks CaM kinases. Moreover, CaN inhibition decreased AChR clustering in Xenopus muscle cells by beads coated with antibodies that cross-link and activate the agrin receptor MuSK (muscle-specific kinase) and reduced the agrin-induced tyrosine phosphorylation of MuSK in cultured mouse (C2) myotubes. Last, the length and the number of AChR clusters generated by agrin in C2 myotubes were decreased by treatment with CsA, but not KN-93, and following the forced expression of a dominant negative CaN mutant in these cells, but not wild-type CaN or reporter green fluorescent protein. Collectively, our results support a role for CaN signaling in the redistribution of AChRs in muscle induced by synaptogenic signals.
Madhavan
Raghavan
R
Department of Biology, Hong King University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Zhao
Xiaotao T
XT
Chan
Frances
F
Wu
Zhenguo
Z
Peng
H Benjamin
HB
D018171:Agrin / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D006133:Growth Substances / Q000494:pharmacology; D008863:Microspheres; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D016559:Tacrolimus / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D014982:Xenopus laevis; D000096926:Benzenesulfonamides
D018171:Agrin; D000906:Antibodies; D001596:Benzylamines; D019703:Calcineurin; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D004791:Enzyme Inhibitors; D006133:Growth Substances; D020794:Receptor Protein-Tyrosine Kinases; D011950:Receptors, Cholinergic; D013449:Sulfonamides; D016559:Tacrolimus; D014443:Tyrosine; C072105:KN 93; D000096926:Benzenesulfonamides; C095714:MUSK protein, human