Rgs4, short for regulator of G-protein signaling 4, is a negative regulator of G-protein signaling. G-protein-coupled receptors (GPCRs) are a large group of membrane proteins, and Rgs4 is crucial for the termination of G protein signals elicited by GPCRs [1,6]. It is involved in multiple cellular responses and plays important roles in various biological processes and diseases. Genetic mouse models have been valuable for studying Rgs4's functions.

In rodent models, Rgs4KO mice show recovery from mechanical and cold allodynia, and increased motivation for wheel running, indicating Rgs4 plays a role in maintaining chronic pain states [2]. In asthma-related studies, RGS4 KO mice have decreased airway hyper-responsiveness (AHR) due to increased production of the bronchodilator prostaglandin E2 (PGE2) by lung epithelial cells, suggesting its role in regulating the airway inflammatory milieu [3]. In cardiac fibrosis models, inhibition of RGS4 expression improved cardiac fibrosis, showing its promoting effect on cardiac fibrosis [4]. In striatal studies, siRNA-mediated knockdown of striatal Rgs4 in diet-induced obesity (DIO)-susceptible rats decreased food intake, highlighting its role in feeding and DIO-susceptibility [5]. In mouse prefrontal cortex studies, knockout of RGS4 increases susceptibility to chronic variable stress (CVS) and paradoxically enhances the antidepressant efficacy of ketamine [7].

In conclusion, Rgs4 is essential in regulating G-protein signaling and impacts numerous biological processes such as pain sensation, airway responsiveness, cardiac fibrosis, feeding behavior, and responses to chronic stress. The Rgs4 KO mouse models have significantly contributed to understanding its roles in these specific disease areas including chronic pain, asthma, cardiac fibrosis, obesity, and mood-related disorders.