L-type channel inactivation balances the increased peak calcium current due to absence of rad in cardiomyocytes

Brooke M. Ahern, Andrea Sebastian, Bryana M. Levitan, Jensen Goh, Douglas A. Andres, Jonathan Satin

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The L-type Ca2+ channel (LTCC) provides trigger calcium to initiate cardiac contraction in a graded fashion that is regulated by L-type calcium current (ICa,L) amplitude and kinetics. Inactivation of LTCC is controlled to fine-tune calcium flux and is governed by voltage-dependent inactivation (VDI) and calcium-dependent inactivation (CDI). Rad is a monomeric G protein that regulates ICa,L and has recently been shown to be critical to β-adrenergic receptor (β-AR) modulation of ICa,L. Our previous work showed that cardiomyocyte-specific Rad knockout (cRadKO) resulted in elevated systolic function, underpinned by an increase in peak ICa,L, but without pathological remodeling. Here, we sought to test whether Rad-depleted LTCC contributes to the fight-or-flight response independently of β-AR function, resulting in ICa,L kinetic modifications to homeostatically balance cardiomyocyte function. We recorded whole-cell ICa,L from ventricular cardiomyocytes from inducible cRadKO and control (CTRL) mice. The kinetics of ICa,L stimulated with isoproterenol in CTRL cardiomyocytes were indistinguishable from those of unstimulated cRadKO cardiomyocytes. CDI and VDI are both enhanced in cRadKO cardiomyocytes without differences in action potential duration or QT interval. To confirm that Rad loss modulates LTCC independently of β-AR stimulation, we crossed a β12-AR double-knockout mouse with cRadKO, resulting in a Rad-inducible triple-knockout mouse. Deletion of Rad in cardiomyocytes that do not express β12-AR still yielded modulated ICa,L and elevated basal heart function. Thus, in the absence of Rad, increased Ca2+ influx is homeostatically balanced by accelerated CDI and VDI. Our results indicate that the absence of Rad can modulate the LTCC without contribution of β12-AR signaling and that Rad deletion supersedes β-AR signaling to the LTCC to enhance in vivo heart function.

Original languageEnglish
Article numbere202012854
JournalJournal of General Physiology
Volume153
Issue number9
DOIs
StatePublished - Sep 6 2021

Bibliographical note

Funding Information:
This research was funded by an American Heart Association predoctoral fellowship to B.M. Ahern (19PRE34380909), a National Institutes of Health/National Heart, Lung, and Blood Institute grant (HL131782), and a U.S. Department of Defense grant (W81WXH-20-1-0418). The authors declare no competing financial interests.

Publisher Copyright:
© 2021 Ahern et al.

ASJC Scopus subject areas

  • Physiology

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