Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 8, Pages 4561-4572Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.573956
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- Deutsche Forschungsgemeinschaft [Hi 800/3-1]
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Expression of the beta-subunit (Ca-V beta) is required for normal function of cardiac L-type calcium channels, and its up-regulation is associated with heart failure. Ca-V beta binds to the alpha(1) poreforming subunit of L-type channels and augments calcium current density by facilitating channel opening and increasing the number of channels in the plasma membrane, by a poorly understood mechanism. Actin, a key component of the intracellular trafficking machinery, interacts with Src homology 3 domains in different proteins. Although Ca-V beta encompasses a highly conserved Src homology 3 domain, association with actin has not yet been explored. Here, using co-sedimentation assays and FRET experiments, we uncover a direct interaction between Ca-V beta and actin filaments. Consistently, single-molecule localization analysis reveals streaklike structures composed by Ca-V beta(2) that distribute over several micrometers along actin filaments in HL-1 cardiomyocytes. Overexpression of Ca-V beta(2)-N3 in HL-1 cells induces an increase in L-type current without altering voltage-dependent activation, thus reflecting an increased number of channels in the plasma membrane. Ca-V beta mediated L-type up-regulation, and Ca-V beta-actin association is prevented by disruption of the actin cytoskeleton with cytochalasin D. Our study reveals for the first time an interacting partner of Ca-V beta that is directly involved in vesicular trafficking. We propose a model in which Ca-V beta promotes anterograde trafficking of the L-type channels by anchoring them to actin filaments in their itinerary to the plasma membrane.
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