Rad as a novel regulator of excitation-contraction coupling and beta-adrenergic signaling in heart

Circulation Research
Gang WangHeping Cheng

Abstract

Rad (Ras associated with diabetes) GTPase, a monomeric small G protein, binds to Ca(v)beta subunit of the L-type Ca(2+) channel (LCC) and thereby regulates LCC trafficking and activity. Emerging evidence suggests that Rad is an important player in cardiac arrhythmogenesis and hypertrophic remodeling. However, whether and how Rad involves in the regulation of excitation-contraction (EC) coupling is unknown. This study aimed to investigate possible role of Rad in cardiac EC coupling and beta-adrenergic receptor (betaAR) inotropic mechanism. Adenoviral overexpression of Rad by 3-fold in rat cardiomyocytes suppressed LCC current (I(Ca)), [Ca(2+)](i) transients, and contractility by 60%, 42%, and 38%, respectively, whereas the "gain" function of EC coupling was significantly increased, due perhaps to reduced "redundancy" of LCC in triggering sarcoplasmic reticulum release. Conversely, approximately 70% Rad knockdown by RNA interference increased I(Ca) (50%), [Ca(2+)](i) transients (52%) and contractility (58%) without altering EC coupling efficiency; and the dominant negative mutant RadS105N exerted a similar effect on I(Ca). Rad upregulation caused depolarizing shift of LCC activation and hastened time-dependent LCC inactivation; R...Continue Reading

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