title: Nuclear effects of G-protein receptor kinase 5 on histone deacetylase 5-regulated gene transcription in heart failure.
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.
  
  
  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.
authors.affiliation: Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Scot J
authors.initials: SJ
authors.lastname: Matkovich
authors.forename: Xiujun
authors.initials: X
authors.lastname: Duan
authors.forename: Jessica I
authors.initials: JI
authors.lastname: Gold
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000502:physiology; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D000804:Angiotensin II; D049452:Green Fluorescent Proteins; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11