ArticleCirculation research2013
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.
Article in Circulation research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers.
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Who cites it
91 citing papers in PubMed, 133 citations in OpenAlex.
- Beyond β-Adrenergic Receptor Brake: Compartment-Selective GRK2 Programs from Heart Failure to Cardio-Oncology.Kinases and phosphatases · 2026Article
- Analysis of GRK2 aggregation in the pathology of Alzheimer disease in animal models.Cell reports. Medicine · 2026Article
- Cys340Ser Mutation Abolishing S-Nitrosylation Drives GRK2 Mitochondrial Localization and Dysfunction.Cells · 2026Article
- Mitochondrial remodeling in heart failure with reduced ejection fraction.Frontiers in physiology · 2026Review
- miR-181a post-transcriptionally targets GRK2 to limit maladaptive signaling in cardiomyocytes.Frontiers in cardiovascular medicine · 2026Article
- Mitochondrial accumulation of GRK2 as a protective mechanism against hypoxia-induced endothelial dysfunction.Cell death discovery · 2025Article
- GRK2 and Mitochondrial Dynamics in Cardiovascular Health and Disease.International journal of molecular sciences · 2025Review
- Canonical or non-canonical, all aspects of G protein-coupled receptor kinase 2 in heart failure.Acta physiologica (Oxford, England) · 2025Review
- Unheralded Adrenergic Receptor Signaling in Cellular Oxidative Stress and Death.Current opinion in physiology · 2024Article
- Exploring the role of pyroptosis in the pathogenicity of heart disease.Frontiers in physiology · 2024Review
- Novel roles for G protein-coupled receptor kinases in cardiac injury and repair.Biochemical Society transactions · 2023Review
- Downregulation of G protein-coupled receptor kinase 4 protects against kidney ischemia-reperfusion injury.Kidney international · 2023Article
- Loss of cholinergic receptor muscarinic 1 impairs cortical mitochondrial structure and function: implications in Alzheimer's disease.Frontiers in cell and developmental biology · 2023Article
- GRK2 in cardiovascular disease and its potential as a therapeutic target.Journal of molecular and cellular cardiology · 2022Review
- Pharmacotherapy of Itch-Antihistamines and Histamine Receptors as G Protein-Coupled Receptors.International journal of molecular sciences · 2022Review
- Double life: How GRK2 and β-arrestin signaling participate in diseases.Cellular signalling · 2022Review
- Sex Differences in Cardiovascular Diseases: A Matter of Estrogens, Ceramides, and Sphingosine 1-Phosphate.International journal of molecular sciences · 2022Review
- Myocardial GRK2 Reduces Fatty Acid Metabolism and β-Adrenergic Receptor-Mediated Mitochondrial Responses.International journal of molecular sciences · 2022Article
- Disruption of actin dynamics induces autophagy of the eukaryotic chaperonin TRiC/CCT.Cell death discovery · 2022Article
- The Potential of Hsp90 in Targeting Pathological Pathways in Cardiac Diseases.Journal of personalized medicine · 2021Review
31 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
rationaleG 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.
objectiveThe 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. METHODS AND
resultsUsing 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.
conclusionsWe identify GRK2 as a prodeath kinase in the heart, acting in a novel manner through mitochondrial localization via extracellular signal-regulated kinase regulation.
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