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

Circ Heart Fail. 2011 Sep;4(5):659-68. doi: 10.1161/CIRCHEARTFAILURE.111.962563. Epub 2011 Jul 18.

Abstract

Background: 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.

Methods and results: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin II / metabolism
  • Animals
  • Cell Nucleus / metabolism*
  • Cytoplasm / metabolism
  • Disease Models, Animal
  • G-Protein-Coupled Receptor Kinase 5 / genetics
  • G-Protein-Coupled Receptor Kinase 5 / metabolism*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Heart Failure / genetics*
  • Heart Failure / metabolism*
  • Heart Failure / physiopathology
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphorylation / physiology
  • Sequence Analysis, RNA
  • Transcription, Genetic / physiology*

Substances

  • Angiotensin II
  • Green Fluorescent Proteins
  • G-Protein-Coupled Receptor Kinase 5
  • GRK5 protein, human
  • Hdac5 protein, mouse
  • Histone Deacetylases
  • GTP-Binding Protein alpha Subunits, Gq-G11