4.7 Article

Nanoenviroments of the β-Subunit of L-Type Voltage-Gated Calcium Channels in Adult Cardiomyocytes

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出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2021.724778

关键词

APEX-mediated proximity labeling; cardiomyocytes; protein-protein interaction; ryanodine receptor; beta-subunit voltage-gated calcium channels; calcium-induced calcium release

资金

  1. German Research Foundation [DFG MI 2114/1-1, MA3257/ 8-1, DFG Ma 2528/7-1, SFB 894, TRR-219]
  2. Interdisciplinary Centre for Clinical Research Wurzburg [IZKF E-332]
  3. German Federal Agency for Education and Research [BMBF 01EO1504]

向作者/读者索取更多资源

Ca2+ influx through LTCCs in cardiomyocytes plays a crucial role in regulating Ca2+-dependent processes. In this study, proximity labeling and quantitative proteomics were used to identify proteins associated with Ca-v beta(2) in cardiomyocytes. These proteins are involved in diverse cellular functions. Additionally, interaction between Ca-v beta(2) and RyR2 was found to be necessary for the Ca2+-induced Ca2+ release mechanism in cardiomyocytes.
In cardiomyocytes, Ca2+ influx through L-type voltage-gated calcium channels (LTCCs) following membrane depolarization regulates crucial Ca2+-dependent processes including duration and amplitude of the action potentials and excitation-contraction coupling. LTCCs are heteromultimeric proteins composed of the Ca-v alpha(1), Ca-v beta, Ca-v alpha(2)delta and Ca-v gamma subunits. Here, using ascorbate peroxidase (APEX2)-mediated proximity labeling and quantitative proteomics, we identified 61 proteins in the nanoenvironments of Ca-v beta(2) in cardiomyocytes. These proteins are involved in diverse cellular functions such as cellular trafficking, cardiac contraction, sarcomere organization and excitation-contraction coupling. Moreover, pull-down assays and co-immunoprecipitation analyses revealed that Ca-v beta(2) interacts with the ryanodine receptor 2 (RyR2) in adult cardiomyocytes, probably coupling LTCCs and the RyR2 into a supramolecular complex at the dyads. This interaction is mediated by the Src-homology 3 domain of Ca-v beta(2) and is necessary for an effective pacing frequency-dependent increase of the Ca2+-induced Ca2+ release mechanism in cardiomyocytes.

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