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Direct interaction of CaVbeta with actin up-regulates L-type calcium currents in HL-1 cardiomyocytes.

Authors: Stolting, G  De Oliveira, RC  Guzman, RE  Miranda-Laferte, E  Conrad, R  Jordan, N  Schmidt, S  Hendriks, J  Gensch, T  Hidalgo, P 
Citation: Stolting G, etal., J Biol Chem. 2015 Feb 20;290(8):4561-72. doi: 10.1074/jbc.M114.573956. Epub 2014 Dec 22.
Pubmed: (View Article at PubMed) PMID:25533460
DOI: Full-text: DOI:10.1074/jbc.M114.573956

Expression of the beta-subunit (CaVbeta) is required for normal function of cardiac L-type calcium channels, and its up-regulation is associated with heart failure. CaVbeta binds to the alpha1 pore-forming 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 CaVbeta 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 CaVbeta and actin filaments. Consistently, single-molecule localization analysis reveals streaklike structures composed by CaVbeta2 that distribute over several micrometers along actin filaments in HL-1 cardiomyocytes. Overexpression of CaVbeta2-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. CaVbeta mediated L-type up-regulation, and CaVbeta-actin association is prevented by disruption of the actin cytoskeleton with cytochalasin D. Our study reveals for the first time an interacting partner of CaVbeta that is directly involved in vesicular trafficking. We propose a model in which CaVbeta 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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CRRD Object Information
CRRD ID: 11059570
Created: 2016-04-16
Species: All species
Last Modified: 2016-04-16
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.