title: Caveolin-3 promotes nicotinic acetylcholine receptor clustering and regulates neuromuscular junction activity.
abstract: 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.
authors: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors: Michael
authors: M
authors: Hezel
authors: William C
authors: WC
authors: de Groat
authors: Ferruccio
authors: F
authors: Galbiati
mesh_terms: 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
chemical_list: D018171:Agrin; D051244:Caveolin 3; D011978:Receptors, Nicotinic; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D020830:rac1 GTP-Binding Protein