Cardiac Ca V 1.2 channels require β subunits for β-adrenergic–mediated modulation but not trafficking

Lin Yang, Alexander Katchman, Jared Kushner, Alexander Kushnir, Sergey I. Zakharov, Bi xing Chen, Zunaira Shuja, Prakash Subramanyam, Guoxia Liu, Arianne Papa, Daniel Roybal, Geoffrey S. Pitt, Henry M. Colecraft, Steven O. Marx

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Ca 2+ 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 α 1C subunits lacking capacity to bind Ca V β can traffic to the sarcolemma in adult cardiomyocytes in vivo and sustain normal excitation-contraction coupling. However, these β-less Ca 2+ 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 Ca 2+ 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 Ca V 1.2 channels and positive inotropy in the heart, but are dispensable for Ca V 1.2 trafficking to the adult cardiomyocyte cell surface, and for basal function and excitation-contraction coupling.

Original languageEnglish (US)
Pages (from-to)647-658
Number of pages12
JournalJournal of Clinical Investigation
Volume129
Issue number2
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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