Caveolin-3 promotes nicotinic acetylcholine receptor clustering and regulates neuromuscular junction activity.
The molecular mechanisms that regulate the organization and activity of the neuromuscular junction remain to be fully identified. Caveolae are invaginations of the plasma membrane. Caveolin-3 is the structural protein component of caveolae in muscle cells. We show that caveolin-3 is expressed at the neuromuscular junction, that it associates with the nicotinic acetylcholine receptor (nAChR), and that a lack of caveolin-3 inhibits clustering of the nAChR in myotubes. At the molecular level, we demonstrate that caveolin-3 is a novel muscle-specific kinase (MuSK) binding protein and that altered nAChR clustering in caveolin-3-lacking myotubes results from inhibition of agrin-induced phosphorylation/activation of MuSK and activation of Rac-1. Functional studies in caveolin-3 null mice show abnormal neuromuscular junction activity that is consistent with altered nAChR localization at the sarcolemma. Together, these data identify caveolin-3 as a critical component of the signaling machinery that drives nicotinic acetylcholine receptor clustering and controls neuromuscular junction function.
Hezel
Michael
M
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
de Groat
William C
WC
Galbiati
Ferruccio
F
D018171:Agrin / Q000494:pharmacology; D000818:Animals; D051244:Caveolin 3 / Q000172:deficiency / Q000378:metabolism*; D002478:Cells, Cultured; D004576:Electromyography; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D018171:Agrin; D051244:Caveolin 3; D011978:Receptors, Nicotinic; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D020830:rac1 GTP-Binding Protein