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Cardiac CaV1.2 channels require β subunits for β-adrenergic–mediated modulation but not trafficking
Lin Yang, … , Henry M. Colecraft, Steven O. Marx
Lin Yang, … , Henry M. Colecraft, Steven O. Marx
Published February 1, 2019; First published November 13, 2018
Citation Information: J Clin Invest. 2019;129(2):647-658. https://doi.org/10.1172/JCI123878.
View: Text | PDF
Categories: Research Article Cardiology Muscle biology

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

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Abstract

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.

Authors

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

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