Rad-GTPase contributes to heart rate via L-type calcium channel regulation

Bryana M. Levitan, Brooke M. Ahern, Ajoy Aloysius, Laura Brown, Yuan Wen, Douglas A. Andres, Jonathan Satin

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Sinoatrial node cardiomyocytes (SANcm) possess automatic, rhythmic electrical activity. SAN rate is influenced by autonomic nervous system input, including sympathetic nerve increases of heart rate (HR) via activation of β-adrenergic receptor signaling cascade (β-AR). L-type calcium channel (LTCC) activity contributes to membrane depolarization and is a central target of β-AR signaling. Recent studies revealed that the small G-protein Rad plays a central role in β-adrenergic receptor directed modulation of LTCC. These studies have identified a conserved mechanism in which β-AR stimulation results in PKA-dependent Rad phosphorylation: depletion of Rad from the LTCC complex, which is proposed to relieve the constitutive inhibition of CaV1.2 imposed by Rad association. Here, using a transgenic mouse model permitting conditional cardiomyocyte selective Rad ablation, we examine the contribution of Rad to the control of SANcm LTCC current (ICa,L) and sinus rhythm. Single cell analysis from a recent published database indicates that Rad is expressed in SANcm, and we show that SANcm ICa,L was significantly increased in dispersed SANcm following Rad silencing compared to those from CTRL hearts. Moreover, cRadKO SANcm ICa,L was not further increased with β-AR agonists. We also evaluated heart rhythm in vivo using radiotelemetered ECG recordings in ambulating mice. In vivo, intrinsic HR is significantly elevated in cRadKO. During the sleep phase cRadKO also show elevated HR, and during the active phase there is no significant difference. Rad-deletion had no significant effect on heart rate variability. These results are consistent with Rad governing LTCC function under relatively low sympathetic drive conditions to contribute to slower HR during the diurnal sleep phase HR. In the absence of Rad, the tonic modulated SANcm ICa,L promotes elevated sinus HR. Future novel therapeutics for bradycardia targeting Rad – LTCC can thus elevate HR while retaining βAR responsiveness.

Original languageEnglish
Pages (from-to)60-69
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume154
DOIs
StatePublished - May 2021

Bibliographical note

Funding Information:
This research was funded by National Institutes of Health (NIH), NHLBI R01 HL131782 (DAA, JS), Department of Defense , United States W81XWH-20-1-0418 (DAA, JS), AHA pre-doctoral fellowship to BMA ( 19PRE34380909 ), and Institutional Development Award (IDeA) from NIH NIGMS P30 GM127211 .

Publisher Copyright:
© 2021 Elsevier Ltd

Keywords

  • Cardiomyocyte
  • Heart rate regulation
  • Heart rhythm
  • L-type calcium channel

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'Rad-GTPase contributes to heart rate via L-type calcium channel regulation'. Together they form a unique fingerprint.

Cite this