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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
Journal article   Open access   Peer reviewed

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

Mai Chen, Priscila Y. Sato, J. Kurt Chuprun, Raymond J. Peroutka, Nicholas J. Otis, Jessica Ibetti, Shi Pan, Shey-Shing Sheu, Erhe Gao and Walter J. Koch
Circulation research, v 112(8), pp 1121-1134
12 Apr 2013
DOI: https://doi.org/10.1161/CIRCRESAHA.112.300754
PMID: 23467820
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.112.300754View
Published, Version of Record (VoR) Open
url
https://doi.org/10.1161/CIRCRESAHA.112.300754View
Published, Version of Record (VoR) Open

Abstract

Cardiac & Cardiovascular Systems Cardiovascular System & Cardiology Hematology Life Sciences & Biomedicine Peripheral Vascular Disease Science & Technology
Rationale: 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 beta-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 beta-adrenergic receptor kinase. Methods and 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 Ca2+-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. (Circ Res. 2013; 112: 1121-1134.)

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115 citations in Scopus

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Cardiac & Cardiovascular Systems
Hematology
Peripheral Vascular Disease
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