Rad-GTPase contributes to heart rate via L-type calcium channel regulation. (May 2021)

• Record Type: Journal Article
• Authors: Levitan, Bryana M.; Ahern, Brooke M.; Aloysius, Ajoy; Brown, Laura; Wen, Yuan; Andres, Douglas A.; Satin, Jonathan
• Is Part Of: Journal of molecular and cellular cardiology. Volume 154(2021)
• Page Start: 60
• Page End: 69
• Publication Date: 2021-05
• Subjects: L-type calcium channel -- Cardiomyocyte -- Heart rhythm -- Heart rate regulation; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2021.01.005
• Languages: English
• ISSNs: 0022-2828

Abstract

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 CaV 1.2 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. Graphical abstract: Image 1 Highlights: SAN cardiomyocytes express Rad. Rad deletion in SAN cardiomyocytes increases ICa, L consistent with Rad's role as an endogenous LTCC governor. Rad regulates intrinsic HR consistent with βAR modulated ICa, L regulation. HR during the sleep cycle is selectively elevated by Rad deletion. Rad – LTCC association may be a useful target for future therapeutics to treat symptomatic bradycardia.