title: Prodeath signaling of G protein-coupled receptor kinase 2 in cardiac myocytes after ischemic stress occurs via extracellular signal-regulated kinase-dependent heat shock protein 90-mediated mitochondrial targeting.
abstract: BACKGROUND
  G protein-coupled receptor kinase 2 (GRK2) is abundantly expressed in the heart, and its expression and activity are increased in injured or stressed myocardium. This upregulation has been shown to be pathological. GRK2 can promote cell death in ischemic myocytes, and its inhibition by a peptide comprising the last 194 amino acids of GRK2 (known as carboxyl-terminus of β-adrenergic receptor kinase [bARKct]) is cardioprotective.
  
  
  OBJECTIVE
  The aim of this study was to elucidate the signaling mechanism that accounts for the prodeath signaling seen in the presence of elevated GRK2 and the cardioprotection afforded by the carboxyl-terminus of β-adrenergic receptor kinase.
  
  
  RESULTS
  Using in vivo mouse models of ischemic injury and also cultured myocytes, we found that GRK2 localizes to mitochondria, providing novel insight into GRK2-dependent pathophysiological signaling mechanisms. Mitochondrial localization of GRK2 in cardiomyocytes was enhanced after ischemic and oxidative stress, events that induced prodeath signaling. Localization of GRK2 to mitochondria was dependent on phosphorylation at residue Ser670 within its extreme carboxyl-terminus by extracellular signal-regulated kinases, resulting in enhanced GRK2 binding to heat shock protein 90, which chaperoned GRK2 to mitochondria. Mechanistic studies in vivo and in vitro showed that extracellular signal-regulated kinase regulation of the C-tail of GRK2 was an absolute requirement for stress-induced, mitochondrial-dependent prodeath signaling, and blocking this led to cardioprotection. Elevated mitochondrial GRK2 also caused increased Ca(2+)-induced opening of the mitochondrial permeability transition pore, a key step in cellular injury.
  
  
  CONCLUSIONS
  We identify GRK2 as a prodeath kinase in the heart, acting in a novel manner through mitochondrial localization via extracellular signal-regulated kinase regulation.
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Mai
authors: M
authors: Chen
authors: Priscila Y
authors: PY
authors: Sato
authors: J Kurt
authors: JK
authors: Chuprun
authors: Raymond J
authors: RJ
authors: Peroutka
authors: Nicholas J
authors: NJ
authors: Otis
authors: Jessica
authors: J
authors: Ibetti
authors: Shi
authors: S
authors: Pan
authors: Shey-Shing
authors: SS
authors: Sheu
authors: Erhe
authors: E
authors: Gao
authors: Walter J
authors: WJ
authors: Koch
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002417:Cattle; D002478:Cells, Cultured; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
chemical_list: D018841:HSP90 Heat-Shock Proteins; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2