Uncovering G protein-coupled receptor kinase-5 as a novel histone deacetylase kinase
G Protein-coupled receptor (GPCR) kinases (GRKs) are critical regulators of cellular signaling and function. In cardiomyocytes GRK2 and GRK5 are two GRKs important for myocardial regulation and both have been shown to be up-regulated in the dysfunctional heart. We report that increased levels and activity of GRK5 in failing myocardium may have unique significance due to its nuclear localization, a property not shared by GRK2. We find that transgenic mice with elevated cardiac GRK5 levels have exaggerated hypertrophy and early heart failure compared to control mice after pressure overload This pathology is not present in cardiac GRK2 overexpressing mice or mice with overexpression of a mutant GRK5 that is excluded from the nucleus. We show that nuclear accumulation of GRK5 is enhanced in myocytes after aortic banding in vivo and also in vitro in myocytes after increased Gαq activity, the trigger for pressure overload hypertrophy. GRK5 enhances activation of myocyte enhancer factor-2 (MEF2) in concert with Gq signals demonstrating that nuclear localized GRK5 regulates gene transcription via a pathway critically linked to myocardial hypertrophy. Mechanistically we show that this is due to GRK5 acting, in a non-GPCR manner, as a Class II histone deacetylase (HDAC) kinase as it can associate with and phosphorylate the MEF2 repressor, HDAC5. Moreover, significant HDAC activity can be found with GRK5 immunoprecipitated from hypertrophied hearts. Finally, our preliminary data suggests that calmodulin binding to GRK5 at amino acids 30 and 31 within the amino terminal region is a prerequisite for GRK5 nuclear accumulation. Taken together, our data show that GRK5 is a novel nuclear HDAC kinase that plays a key role in maladaptive cardiac hypertrophy apparently independent of any action directly on GPCRs. ^
Jeffrey S Martini,
"Uncovering G protein-coupled receptor kinase-5 as a novel histone deacetylase kinase"
(January 1, 2008).
ETD Collection for Thomas Jefferson University.