title: RGS-Insensitive G Proteins as In Vivo Probes of RGS Function.
abstract: Guanine nucleotide-binding proteins of the inhibitory (Gi/o) class play critical physiological roles and the receptors that activate them are important therapeutic targets (e.g., mu opioid, serotonin 5HT1a, etc.). Gi/o proteins are negatively regulated by regulator of G protein signaling (RGS) proteins. The redundant actions of the 20 different RGS family members have made it difficult to establish their overall physiological role. A unique G protein mutation (G184S in Gαi/o) prevents RGS binding to the Gα subunit and blocks all RGS action at that particular Gα subunit. The robust phenotypes of mice expressing these RGS-insensitive (RGSi) mutant G proteins illustrate the profound action of RGS proteins in cardiovascular, metabolic, and central nervous system functions. Specifically, the enhanced Gαi2 signaling through the RGSi Gαi2(G184S) mutant knock-in mice shows protection against cardiac ischemia/reperfusion injury and potentiation of serotonin-mediated antidepressant actions. In contrast, the RGSi Gαo mutant knock-in produces enhanced mu-opioid receptor-mediated analgesia but also a seizure phenotype. These genetic models provide novel insights into potential therapeutic strategies related to RGS protein inhibitors and/or G protein subtype-biased agonists at particular GPCRs.
authors.affiliation: Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, USA. Electronic address: RNeubig@msu.edu.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
mesh_terms: D000818:Animals; D019204:GTP-Binding Proteins / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D055786:Gene Knockout Techniques; D006801:Humans; D008957:Models, Genetic; D010641:Phenotype; D020710:RGS Proteins / Q000378:metabolism*
chemical_list: D020710:RGS Proteins; D019204:GTP-Binding Proteins
keywords: Depression; Epilepsy; G protein; Genetics; Heart; Regulator of G protein signaling