Expression of the muscular dystrophy-associated caveolin-3(P104L) mutant in adult mouse skeletal muscle specifically alters the Ca(2+) channel function of the dihydropyridine receptor.
Caveolins are plasma-membrane-associated proteins potentially involved in a variety of signalling pathways. Different mutations in CAV3, the gene encoding for the muscle-specific isoform caveolin-3 (Cav-3), lead to muscle diseases, but the underlying molecular mechanisms remain largely unknown. Here, we explored the functional consequences of a Cav-3 mutation (P104L) inducing the 1C type limb-girdle muscular dystrophy (LGMD 1C) in human on intracellular Ca(2+) regulation of adult skeletal muscle fibres. A YFP-tagged human Cav-3(P104L) mutant was expressed in vivo in muscle fibres from mouse. Western blot analysis revealed that expression of this mutant led to an approximately 80% drop of the level of endogenous Cav-3. The L-type Ca(2+) current density was found largely reduced in fibres expressing the Cav-3(P104L) mutant, with no change in the voltage dependence of activation and inactivation. Interestingly, the maximal density of intramembrane charge movement was unaltered in the Cav-3(P104L)-expressing fibres, suggesting no change in the total amount of functional voltage-sensing dihydropyridine receptors (DHPRs). Also, there was no obvious alteration in the properties of voltage-activated Ca(2+) transients in the Cav-3(P104L)-expressing fibres. Although the actual role of the Ca(2+) channel function of the DHPR is not clearly established in adult skeletal muscle, its specific alteration by the Cav-3(P104L) mutant suggests that it may be involved in the physiopathology of LGMD 1C.
Weiss
Norbert
N
Physiologie Intégrative Cellulaire et Moléculaire, Université Claude Bernard-Lyon 1,Villeurbanne Cedex, France.
Couchoux
Harold
H
Legrand
Claude
C
Berthier
Christine
C
Allard
Bruno
B
Jacquemond
Vincent
V
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D018274:Electroporation; D018014:Gene Transfer Techniques; D006801:Humans; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation; D011993:Recombinant Fusion Proteins / Q000378:metabolism
C417736:CAV3 protein, human; D020746:Calcium Channels, L-Type; C495548:Cav3 protein, mouse; D051244:Caveolin 3; D011993:Recombinant Fusion Proteins