Cardiac CaV1.2 channels require β subunits for β-adrenergic-mediated modulation but not trafficking.

Published

Journal Article

Ca2+ channel β-subunit interactions with pore-forming α-subunits are long-thought to be obligatory for channel trafficking to the cell surface and for tuning of basal biophysical properties in many tissues. Unexpectedly, we demonstrate that transgenic expression of mutant α1C subunits lacking capacity to bind CaVβ can traffic to the sarcolemma in adult cardiomyocytes in vivo and sustain normal excitation-contraction coupling. However, these β-less Ca2+ channels cannot be stimulated by β-adrenergic pathway agonists, and thus adrenergic augmentation of contractility is markedly impaired in isolated cardiomyocytes and in hearts. Similarly, viral-mediated expression of a β-subunit-sequestering peptide sharply curtailed β-adrenergic stimulation of WT Ca2+ channels, identifying an approach to specifically modulate β-adrenergic regulation of cardiac contractility. Our data demonstrate that β subunits are required for β-adrenergic regulation of CaV1.2 channels and positive inotropy in the heart, but are dispensable for CaV1.2 trafficking to the adult cardiomyocyte cell surface, and for basal function and excitation-contraction coupling.

Full Text

Duke Authors

Cited Authors

  • Yang, L; Katchman, A; Kushner, J; Kushnir, A; Zakharov, SI; Chen, B-X; Shuja, Z; Subramanyam, P; Liu, G; Papa, A; Roybal, D; Pitt, GS; Colecraft, HM; Marx, SO

Published Date

  • February 1, 2019

Published In

Volume / Issue

  • 129 / 2

Start / End Page

  • 647 - 658

PubMed ID

  • 30422117

Pubmed Central ID

  • 30422117

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI123878

Language

  • eng

Conference Location

  • United States