The therapeutic potential of targeting cardiac RGS4

Abstract

G protein-coupled receptors (GPCRs) play pivotal roles in regulation of cardiac function and homeostasis. To function properly, every cell needs these receptors to be stimulated only when a specific extracellular stimulus is present, and to be silenced the moment that stimulus is removed. The regulator of G protein signaling (RGS) proteins are crucial for the latter to occur at the cell membrane, where the GPCR normally resides. Perturbations in both activation and termination of G protein signaling underlie numerous heart pathologies. Although more than 30 mammalian RGS proteins have been identified, each RGS protein seems to interact only with a specific set of G protein subunits and GPCR types/subtypes in any given tissue or cell type, and this applies to the myocardium as well. A large number of studies have provided substantial evidence for the roles various RGS proteins expressed in cardiomyocytes play in cardiac physiology and heart disease pathophysiology. This review summarizes the current understanding of the functional roles of cardiac RGS proteins and their implications for the treatment of specific heart diseases, such as heart failure and atrial fibrillation. We focus on cardiac RGS4 in particular, since this isoform appears to be selectively (among the RGS protein family) upregulated in human heart failure and is also the target of ongoing drug discovery efforts for the treatment of a variety of diseases.

Keywords: G protein-coupled receptor; G proteins; arrhythmias; atrial fibrillation; cardiac myocyte; cyclic AMP; heart failure; regulator of G protein signaling; signal transduction.

Figure 1.

Role of cardiomyocyte RGS4 in the context of human HF. Basal and hormone induced (e.g. by adenosine A₁ and A₃ or M₂ muscarinic cholinergic receptors) Gαi activity is elevated, so cAMP levels are low in human HF. RGS4, by accelerating GTP hydrolysis on Gαi, functionally opposes/terminates Gαi actions, thereby (indirectly) promoting AC activation and cAMP synthesis. cAMP exerts multiple effects in the heart crucial for cardiomyocyte function, such as contraction followed by relaxation, automaticity, and positive chronotropy and dromotropy (conduction). Thus, RGS4 can potentially reverse part of the molecular abnormalities present in the failing human myocardium. A, adenine; AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, 3′,5′-adenosine monophosphate; G, guanine; HF, heart failure; P, phosphorylation; Pi, inorganic phosphate; RGS, regulator of G protein signaling. See text for more details and all other molecular acronym descriptions.

Figure 2.

Role of (atrial) cardiomyocyte RGS4 in the context of human AFib. RGS4 terminates Gq protein signaling induced by AngII and ET-1 receptors, thereby attenuating pro-arrhythmic calcium signaling and reducing risk of AFib development. ACh, acetylcholine; AFib, atrial fibrillation; AngII, angiotensin II; ET-1, endothelin-1; HR, heart rate; IP₃, inositol 1′,4′,5′-trisphosphate; RGS, regulator of G protein signaling. See text for more details and all other molecular acronym descriptions.