G Protein-Coupled Receptor Kinase 5 is a Novel Requirement for Maladpative Cardiac Remodeling and Heart Failure
Abstract
G protein Coupled Receptor (GPCR) Kinase 5 (GRK5) is one of two primary GRKs expressed in cardiomyocytes. Its traditional role is to phosphorylate agonist-bound GPCRs, creating a docking space for arrestin. Arrestins bind and remove GPCRs from the plasma membrane, targeting the GPCR either for internalization or degradation. This desensitization is especially important in the heart following cardiac injury. Recent, exciting data from the Koch lab has shown GRK5 playing a role beyond the desensitization pathway. Specifically, there is evidence that GRK5 translocates into the nucleus and phosphorylates the Class II Histone Deacetylase 5 (HDAC5). This HDAC kinase activity of GRK5 causes nuclear export of HDAC5 in cardiomyocytes, lifting its repression on gene transcription and enhancing expression of hypertrophic genes. We explored the mechanism behind GRK5 nuclear translocation and its effect on maladaptive cardiac hypertrophy and subsequent heart failure (HF) using cell culture, genetically engineered mice and surgical models of cardiac pathology. Our central hypothesis was that nuclear GRK5 localization and activity plays a critical and detrimental role in cardiomyocytes, causing pathological hypertrophy and HF, and that signaling by hypertrophic stimuli increases GRK5 nuclear translocation. We determined that select Gq-coupled receptor activation causes GRK5 to leave the plasma membrane and accumulate in the nucleus due to calmodulin (CaM) binding at the amino-terminal of GRK5. A mutant GRK5 unable to bind CaM at its amino-terminal does not enter the nucleus and diminishes cardiac hypertrophy caused by continuous exposure to hypertrophic agonists. We also stressed GRK5 knockout mice using a surgical model of pressure-overload or through continuous adrenergic stimulation. Ablation of cardiomyocyte GRK5 in vivo attenuates cardiac hypertrophy, delays HF onset, and reduces molecular remodeling. Our results show an absolute requirement of GRK5 for maladapative hypertrophy and HF. Clearly, GRK5 plays a pathological role in the heart and preventing its nuclear accumulation would be a novel therapeutic strategy.
Subject Area
Pharmacology
Recommended Citation
Gold, Jessica I, "G Protein-Coupled Receptor Kinase 5 is a Novel Requirement for Maladpative Cardiac Remodeling and Heart Failure" (2012). ProQuest ETD Collection - Thomas Jefferson University. AAI3508404.
https://jdc.jefferson.edu/dissertations/AAI3508404
