Nuclear effects of G-protein receptor kinase 5 on histone deacetylase 5-regulated gene transcription in heart failure.

ABSTRACT: G-protein receptor kinases (GRKs) modulate cardiac ?-adrenergic signaling. GRK5 is upregulated in heart failure, and a gain-of-function polymorphism substituting leucine for wild-type glutamine at amino acid 41 (GRK5-Leu41) is associated with improved outcomes in heart failure and hypertension. GRK5 is distinguished by partial nuclear localization and class II histone deacetylases (HDAC) kinase activity that is postulated to regulate G?q-stimulated cardiac gene expression.We used in vitro tissue culture and in vivo mouse compound genetic models to examine the effects of GRK5 on HDAC phosphorylation, nucleo-cytoplasmic HDAC transport, and G?q-dependent transcriptional regulation. In vitro, GRK5 stimulated HDAC5 nuclear export only in the context of G?q signaling stimulated by angiotensin II. GRK5-Gln41 and Leu41 were similar inducers of HDAC5 nucleo-cytoplasmic shuttling. In vivo, GRK5-Gln41 and-Leu41 partitioned equally to nuclear and nonnuclear myocardial fractions. GRK5 increased cardiac HDAC5 phosphorylation and reversed the increase in nuclear HDAC5 content seen with cardiomyocyte-autonomous G?q overexpression. Deep RNA sequencing showed few changes in gene expression induced by GRK5 overexpression or ablation alone, but GRK5 overexpression normalized steady-state expression levels of 48% (96 of 200) of all G?q down-regulated mRNAs.GRK5 is a transcriptional modifier of a subset of G?q-downregulated genes, acting in opposition to the pathological effects of G?q and normalizing levels of these transcripts. This transcriptional coregulator effect may act in concert with ?-adrenergic receptor desensitization to protect against heart failure decompensation.

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC3178677 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature