And the Winner Is … RGS4!

Abstract

See related article, pages 527–535 RGS proteins play a major role in controlling G protein signaling. Cifelli et al1 show very high expression of RGS4 in sinoatrial (SA) node in the mouse. Of the 10 RGS proteins expressed supraventricularly, genetic disruption of RGS4 alone produces a profound slowing of I K,Ach turnoff kinetics in SA node and enhanced carbachol-induced bradycardia in vivo. This is accompanied by a loss of rapid desensitization of the I K,Ach current, suggesting a selective action of RGS4 in controlling prolonged vagal responses. This has implications for clinical conditions dependent on cholinergic signals such as atrial fibrillation (AF), vasovagal syncope, and possibly torsades de point. These results make RGS4 an intriguing candidate gene in certain arrhythmias. Approximately 12 years ago, the G protein and G protein–coupled receptor fields were rocked by the discovery of the RGS (regulators of G protein signaling) proteins.2,3 Here was a key regulatory protein family that inhibited G protein signaling but was virtually unknown a year earlier. Very rapidly, the core molecular function of RGS proteins was defined as GTPase accelerator protein activity, which sped the deactivating GTP hydrolysis step,4 which, for G proteins, was notoriously slow. The crystal structure of a complex of Gαi1 and RGS4 “caught in the act” of GTP hydrolysis5 followed shortly thereafter. Cardiac atrial function figured prominently in early studies of RGS proteins. The negative chronotropic actions of acetylcholine via the M2 muscarinic receptor involved activation of the I K,Ach current, which is carried by the G protein–coupled inwardly rectifying K+ (GIRK) channel, composed of a heterotetramer of subunits Kir3.1/Kir3.4. GIRK channels are activated by Gβγ subunits released from Gi/o family proteins. Vagal control of heart rate occurs on a very rapid times scale, with slowing and recovery within single …