Abstract 15544: GRK2 RGS Domain-Specific Interaction With Gαq Inhibits Hypertrophy and Cardiac Dysfunction During Pressure Overload
G protein-coupled receptor (GPCR) kinases (GRK) play a critical role in cardiac function through regulation of GPCR activity. Canonically, GRK2 phosphorylates active GPCRs leading to desensitization and down-regulation of the receptors to regulate signaling in the heart. Mounting evidence, however, supports non-canonical regulation of cardiac function by GRK2 through a dynamic “interactome” in which GRK2 can uncouple GPCRs via novel protein-protein interactions. Several GRK2 interacting partners are important for adaptive and maladaptive myocyte growth including Gq, the signaling trigger for maladaptive cardiac hypertrophy, leading to HF. Importantly, GRK2 contains a putative amino-terminal Regulator of G protein Signaling (RGS) domain, that directly interacts with Gq and appears to inhibit signaling without altering Gq enzymatic activity. In the present study we generated transgenic (Tg) mice with cardiac-specific expression of the RGS domain of GRK2 (βARKrgs) and subjected them to a trans-aortic constriction (TAC) model of pressure overload hypertrophy. The βARKrgs Tg mice exhibited a marked anti-hypertrophic effect, with reduced left ventricular wall thickness and hypertrophic gene expression relative to their littermate controls. Use of genetically engineered lines demonstrated that this was through an interaction of the βARKrgs peptide with Gq-mediated signaling that inhibited hypertrophy as well as the progression to heart failure (HF). These data support our hypothesis that the RGS domain of GRK2 may serve as a non-canonical inhibitor of Gq-mediated hypertrophic signaling in the heart and highlight how this research may pave the way for novel GRK2-based therapeutic approaches to prevent hypertrophy and HF.
Author Disclosures: S.M. Schumacher: None. E. Gao: None. M. Cohen: None. M. Lieu: None. J. Chuprun: None. W.J. Koch: None.
- © 2015 by American Heart Association, Inc.