Loss of caveolin-3 induced by the dystrophy-associated P104L mutation impairs L-type calcium channel function in mouse skeletal muscle cells.
Caveolins are membrane scaffolding proteins that associate with and regulate a variety of signalling proteins, including ion channels. A deficiency in caveolin-3 (Cav-3), the major striated muscle isoform, is responsible for skeletal muscle disorders, such as limb-girdle muscular dystrophy 1C (LGMD 1C). The molecular mechanisms leading to the muscle wasting that characterizes this pathology are poorly understood. Here we show that a loss of Cav-3 induced by the expression of the LGMD 1C-associated mutant P104L (Cav-3(P104L)) provokes a reduction by half of the maximal conductance of the voltage-dependent L-type Ca(2+) channel in mouse primary cultured myotubes and fetal skeletal muscle fibres. Confocal immunomiscrocopy indicated a colocalization of Cav-3 and Ca(v)1.1, the pore-forming subunit of the L-type Ca(2+) channel, at the surface membrane and in the developing T-tubule network in control myotubes and fetal fibres. In myotubes expressing Cav-3(P104L), the loss of Cav-3 was accompanied by a 66% reduction in Ca(v)1.1 mean labelling intensity. Our results suggest that Cav-3 is involved in L-type Ca(2+) channel membrane function and localization in skeletal muscle cells and that an alteration of L-type Ca(2+) channels could be involved in the physiopathological mechanisms of caveolinopathies.
Couchoux
Harold
H
University Lyon 1, CNRS, Laboratory of Integrative, Cellular and Molecular Physiology, Villeurbanne, F-69622, France.
Allard
Bruno
B
Legrand
Claude
C
Jacquemond
Vincent
V
Berthier
Christine
C
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D051244:Caveolin 3 / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004553:Electric Conductivity; D004622:Embryo, Mammalian; D007930:Leucine; D051379:Mice; D032342:Muscle Cells / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000235:genetics*; D009154:Mutation; D011392:Proline; D014018:Tissue Distribution
D020746:Calcium Channels, L-Type; D051244:Caveolin 3; D011392:Proline; D007930:Leucine