The RGS4-Gαq/11 axis in vascular homeostasis: Mechanisms and therapeutic implications.

Abstract

Vascular homeostasis, a dynamic equilibrium maintained by the circulatory system, is fundamental to cardiovascular health. Its dysregulation underlies the pathogenesis of major cardiovascular disorders, including hypertension. G protein-coupled receptors (GPCRs), a versatile family of seven-transmembrane proteins, play a central role in maintaining vascular homeostasis. Upon activation, certain GPCRs couple to Gαq/11 proteins and initiate multiple downstream signaling pathways, thereby regulating vascular tone, structural remodeling, and inflammatory responses. Regulator of G protein signaling 4 (RGS4) functions as a key GTPase-activating protein (GAP) that markedly accelerates GTP hydrolysis by Gαq/11, thereby promoting the timely termination of Gαq/11-mediated signaling. RGS4 therefore plays an important role in maintaining the balance of G protein signaling in the vasculature. Based on the three-dimensional structure of RGS4 (PDB ID: 1AGR), this review systematically delineates the GAP catalytic mechanism of RGS4 and its interactions with downstream effectors, including Gαq/11 and PLCβ. It discusses the pathological role of the RGS4-Gαq/11 signaling axis in major cardiovascular disorders. In addition, from a structural pharmacology perspective, this review surveys the druggable features of RGS4 and reviews previously published in silico docking and molecular dynamics studies of its representative inhibitors, intending to inform potential therapeutic strategies targeting the RGS4-Gαq/11 axis in cardiovascular disease.

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