Protein-coupled receptor kinase 5 exacerbates cardiac pathology through activation of the nuclear factor of activated T cells pathway

Jonathan E Hullmann, Thomas Jefferson University

Abstract

G protein-coupled receptor (GPCR) kinases (GRKs) serve to regulate the contractile function of the heart. The upregulation of both GRK2 and GRK5, the predominant GRKs expressed in the heart, has been shown in failing human myocardium. While the canonical role of GRKs is to desensitize receptors via phosphorylation, it has been demonstrated that GRK5, unlike GRK2, can reside in the nucleus of cardiomyocytes and exert GPCR-independent effects that promote maladaptive cardiac hypertrophy and heart failure (HF). We find that cardiac-specific NFAT luciferase reporter mice crossed with mice that overexpress wild-type GRK5 in a cardiomyocyte specific manner exhibit an increase in NFAT activity both in the basal state as well as after the hypertrophic stressors transaortic constriction and phenylephrine administration. Complimentary to this, GRK5 null mice exhibit less NFAT transcriptional activity after left ventricular pressure-overload as shown by the expression of the NFAT target gene RCAN. Importantly, loss of NFATc3 expression protected GRK5 over-expressing mice from the exaggerated hypertrophy and early progression to HF seen after TAC. Molecular studies suggest that GRK5 acts in concert with NFAT to increase hypertrophic gene transcription in the nucleus and this is a kinase-independent action of GRK5 that may involve its known property of DNA binding. This study provides another non-canonical role for GRK5 in activating the hypertrophic NFAT pathway in cardiomyocytes and may serve as a building block for the development of novel therapeutics which are capable of inhibiting and reversing the progression of HF.

Subject Area

Molecular biology

Recommended Citation

Hullmann, Jonathan E, "Protein-coupled receptor kinase 5 exacerbates cardiac pathology through activation of the nuclear factor of activated T cells pathway" (2016). ETD Collection for Thomas Jefferson University. AAI10044090.
https://jdc.jefferson.edu/dissertations/AAI10044090

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