Research ArticleCardiovascular Biology

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

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Sci. Signal.  22 Mar 2016:
Vol. 9, Issue 420, pp. ra30
DOI: 10.1126/scisignal.aae0549

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GRK2 against heart failure

Sustained high blood pressure causes the heart walls to thicken to deal with the increased load, a process called cardiac hypertrophy. If left unchecked, cardiac hypertrophy leads to heart failure. A particular part of the kinase and scaffolding protein GRK2 inhibits a G protein that promotes cardiac hypertrophy. Schumacher et al. generated mice that overexpressed a peptide of this inhibitory region of GRK2 in the heart. These mice developed less cardiac hypertrophy and retained greater cardiac function under conditions that cause heart failure. Thus, targeting this peptide to the heart could suppress hypertrophic signaling and prevent heart failure.

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.

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