GRK5-mediated exacerbation of pathological cardiac hypertrophy involves facilitation of nuclear NFAT activity.

Rationale: G protein-coupled receptor kinases (GRKs) acting in the cardiomyocyte regulate important signaling events that control cardiac function. Both GRK2 and GRK5, the predominant GRKs expressed in the heart, have been shown to be upregulated in failing human myocardium. Although the canonical role of GRKs is to desensitize G protein-coupled receptors via phosphorylation, it has been demonstrated that GRK5, unlike GRK2, can reside in the nucleus of myocytes and exert G protein-coupled receptor-independent effects that promote maladaptive cardiac hypertrophy and heart failure.