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

TitleCardiac CaV1.2 channels require β subunits for β-adrenergic-mediated modulation but not trafficking.
Publication TypeJournal Article
Year of Publication2019
AuthorsYang 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
JournalJ Clin Invest
Volume129
Issue2
Pagination647-658
Date Published2019 02 01
ISSN1558-8238
KeywordsAnimals, Calcium Channels, L-Type, Guinea Pigs, HEK293 Cells, Humans, Mice, Mice, Transgenic, Myocytes, Cardiac, Protein Transport, Sarcolemma
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.

DOI10.1172/JCI123878
Alternate JournalJ. Clin. Invest.
PubMed ID30422117
PubMed Central IDPMC6355231
Grant ListR01 HL113136 / HL / NHLBI NIH HHS / United States
R01 HL068093 / HL / NHLBI NIH HHS / United States
T32 HL120826 / HL / NHLBI NIH HHS / United States
T32 HL007343 / HL / NHLBI NIH HHS / United States
R01 HL121253 / HL / NHLBI NIH HHS / United States
R01 HL140934 / HL / NHLBI NIH HHS / United States