title: New insights in the regulation of calcium transfers by muscle dystrophin-based cytoskeleton: implications in DMD.
abstract: Calcium mishandling in Duchenne muscular dystrophy (DMD) suggested that dystrophin, a membrane-associated cytoskeleton protein, may regulate calcium-signalling cascades such as calcium entries. Calcium overload in human DMD myotubes is dependent on their contractile activity suggesting the involvement of channels being activated during contraction and/or calcium release. Forced expression of mini-dystrophin in dystrophin-deficient myotubes, reactivates appropriate sarcolemmal expression of dystrophin-associated proteins and restores normal calcium handling in the cytosol. Furthermore, the recombinant mini-dystrophin reduced the store-operated calcium influx across the sarcolemma, and the mitochondrial calcium uptake during this influx. A slow component of calcium release dependent on IP3R, as well as the production of IP3, were also reduced to normal levels by expression of mini-dystrophin. Our studies provide a new model for the convergent regulation of transmembrane calcium influx and IP3-dependent calcium release by the dystrophin-based cytoskeleton (DBC). We also suggest molecular association of such channels with DBC which may provide the scaffold for assembling a multiprotein-signalling complex that modulates the channel activity. This suggests that the loss of this molecular association could participate in the alteration of calcium homeostasis observed in DMD muscle cells.
authors.affiliation: Institut de Physiologie et Biologie Cellulaires, CNRS, UMR-6187, University of Poitiers, 86022, Poitiers, France. Bruno.Constantin@univ-poitiers.fr
authors.forename: Bruno
authors.initials: B
authors.lastname: Constantin
authors.forename: Stéphane
authors.initials: S
authors.lastname: Sebille
authors.forename: Christian
authors.initials: C
authors.lastname: Cognard
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D003599:Cytoskeleton / Q000378:metabolism*; D016189:Dystrophin / Q000502:physiology*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D015220:Calcium Channels; D016189:Dystrophin; D053496:Inositol 1,4,5-Trisphosphate Receptors; D002118:Calcium