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

G-protein receptor kinases (GRKs) modulate cardiac β-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 Gαq-stimulated cardiac gene expression.

GRK5 is a transcriptional modifier of a subset of Gαq-downregulated genes, acting in opposition to the pathological effects of Gαq and normalizing levels of these transcripts. This transcriptional coregulator effect may act in concert with β-adrenergic receptor desensitization to protect against heart failure decompensation.

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 Gαq-dependent transcriptional regulation. In vitro, GRK5 stimulated HDAC5 nuclear export only in the context of Gαq 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 Gαq 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 Gαq down-regulated mRNAs. Conclusions: GRK5 is a transcriptional modifier of a subset of Gαq-downregulated genes, acting in opposition to the pathological effects of Gαq and normalizing levels of these transcripts. This transcriptional coregulator effect may act in concert with β-adrenergic receptor desensitization to protect against heart failure decompensation.