A peptide of the RGS domain of GRK2 binds and inhibits Gα _q to suppress pathological cardiac hypertrophy and dysfunction

Abstract

G protein–coupled receptor (GPCR) kinases (GRKs) play a critical role in cardiac function by regulating GPCR activity. GRK2 suppresses GPCR signaling by phosphorylating and desensitizing active GPCRs, and through protein-protein interactions that uncouple GPCRs from their downstream effectors. Several GRK2 interacting partners, including Gαq, promote maladaptive cardiac hypertrophy, which leads to heart failure, a leading cause of mortality worldwide. The regulator of G protein signaling (RGS) domain of GRK2 interacts with and inhibits Gαq in vitro. We generated TgβARKrgs mice with cardiac-specific expression of the RGS domain of GRK2 and subjected these mice to pressure overload to trigger adaptive changes that lead to heart failure. Unlike their nontransgenic littermate controls, the TgβARKrgs mice exhibited less hypertrophy as indicated by reduced left ventricular wall thickness, decreased expression of genes linked to cardiac hypertrophy, and less adverse structural remodeling. The βARKrgs peptide, but not endogenous GRK2, interacted with Gαq and interfered with signaling through this G protein. These data support the development of GRK2-based therapeutic approaches to prevent hypertrophy and heart failure.

“Freeze, Don’t Move”: How to Arrest a Suspect in Heart Failure – A Review on Available GRK2 Inhibitors

“…These mice show less hypertrophy and less adverse structural remodeling compared with controls (49). In this case, it appears that the beneficial effect is more on Gαq inhibition rather than on GRK2 inhibition.…”

Noncanonical Roles of G Protein-coupled Receptor Kinases in Cardiovascular Signaling

“…In this study, the βARKrgs mice were not only resistant to hypertrophic growth after trans-aortic constriction, providing the same anti-hypertrophic effect as inhibition of Gαq association with GPCRs, but the reduction in fibrosis and molecular remodeling prevented the transition to HF during chronic pressure overload (83). This occurred through an association of βARKrgs, but not full-length GRK2, selectively with Gαq in the heart in a manner that inhibited the activity of the Gαq effector phospholipase C beta (PLCβ) (Figure 1-5).…”

“…The potential impact of an interaction between the GRK2 RGS domain and Gαq was recently investigated in a mouse model of pressure overload-induced hypertrophy and HF in transgenic mice with αMHC-targeted cardiac expression of this domain (residues 45–185, βARKrgs) (83). In this study, the βARKrgs mice were not only resistant to hypertrophic growth after trans-aortic constriction, providing the same anti-hypertrophic effect as inhibition of Gαq association with GPCRs, but the reduction in fibrosis and molecular remodeling prevented the transition to HF during chronic pressure overload (83).…”

“…This occurred through an association of βARKrgs, but not full-length GRK2, selectively with Gαq in the heart in a manner that inhibited the activity of the Gαq effector phospholipase C beta (PLCβ) (Figure 1-5). This interaction was enhanced after pressure overload, presumably through Gαq-coupled GPCR activation driving the association of βARKrgs with dissociated Gαq (83). Importantly, unlike βARKrgs, this study revealed that cardiac restricted overexpression (TgGRK2) or peptide inhibition (TgβARKct) of GRK2 did not alter cardiac hypertrophy, demonstrating that loss or gain of function of the full-length enzyme does not alter cardiac hypertrophic responses.…”

The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development

“…The N-terminal third also contains a regulator of G protein signaling (RGS) homology (RH) domain. It has been demonstrated that the RH domain of GRK2 and GRK3 is able to interact with Gα q , while the RH domain of GRK5 and GRK6 has not been shown to interact with G-proteins [11, 12]. …”