ArticleCirculation research2010
Small molecule disruption of G beta gamma signaling inhibits the progression of heart failure.
Article in Circulation research, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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Who cites it
89 citing papers in PubMed, 132 citations in OpenAlex.
- Recent advances in the development of GRK2 inhibitors: blocking the interaction of GRK2 with its partners.Acta pharmacologica Sinica · 2026Review
- Beyond β-Adrenergic Receptor Brake: Compartment-Selective GRK2 Programs from Heart Failure to Cardio-Oncology.Kinases and phosphatases · 2026Article
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- Structural insights into Phospholipase Cε activity and regulation.The Journal of biological chemistry · 2026Review
- Adrenergic receptors on immune cells in cardiovascular disease: signaling plasticity, biased agonism, and therapeutic opportunities.Frontiers in physiology · 2026Review
- Novel repetitive elements in plant-specific tails of Gγ proteins as the functional unit in G-protein signaling in crops.The Plant cell · 2025Article
- Therapeutic Efficacy of a Novel Pharmacologic GRK2 Inhibitor in Multiple Animal Models of Heart Failure.JACC. Basic to translational science · 2025Article
- Review
- Gallein increases prostaglandin F2α‑induced osteoprotegerin and IL‑6 secretion in osteoblasts.Biomedical reports · 2024Article
- Fluoride and gallein regulate polyphosphate accumulation in dental caries-associatedMicrobiology (Reading, England) · 2024Article
- Novel roles for G protein-coupled receptor kinases in cardiac injury and repair.Biochemical Society transactions · 2023Review
- GRK2 in cardiovascular disease and its potential as a therapeutic target.Journal of molecular and cellular cardiology · 2022Review
- Myocardial TRPC6-mediated ZnNature communications · 2022Article
- G protein-coupled receptor signaling: transducers and effectors.American journal of physiology. Cell physiology · 2022Review
- Paeoniflorin-6'O-benzene sulfonate suppresses fibroblast-like synoviocytes proliferation and migration in rheumatoid arthritis through regulating GRK2-Gβγ interaction.Experimental and therapeutic medicine · 2022Article
- Calcium sensing receptor stimulates breast cancer cell migration via the Gβγ-AKT-mTORC2 signaling pathway.Journal of cell communication and signaling · 2022Article
- Alternative strategies in cardiac preclinical research and new clinical trial formats.Cardiovascular research · 2022Review
- Targeting GRK5 for Treating Chronic Degenerative Diseases.International journal of molecular sciences · 2021Review
- Review
- Loss of dynamic regulation of G protein-coupled receptor kinase 2 by nitric oxide leads to cardiovascular dysfunction with aging.American journal of physiology. Heart and circulatory physiology · 2020Article
29 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
rationaleExcess signaling through cardiac Gbetagamma subunits is an important component of heart failure (HF) pathophysiology. They recruit elevated levels of cytosolic G protein-coupled receptor kinase (GRK)2 to agonist-stimulated beta-adrenergic receptors (beta-ARs) in HF, leading to chronic beta-AR desensitization and downregulation; these events are all hallmarks of HF. Previous data suggested that inhibiting Gbetagamma signaling and its interaction with GRK2 could be of therapeutic value in HF.
objectiveWe sought to investigate small molecule Gbetagamma inhibition in HF. METHODS AND
resultsWe recently described novel small molecule Gbetagamma inhibitors that selectively block Gbetagamma-binding interactions, including M119 and its highly related analog, gallein. These compounds blocked interaction of Gbetagamma and GRK2 in vitro and in HL60 cells. Here, we show they reduced beta-AR-mediated membrane recruitment of GRK2 in isolated adult mouse cardiomyocytes. Furthermore, M119 enhanced both adenylyl cyclase activity and cardiomyocyte contractility in response to beta-AR agonist. To evaluate their cardiac-specific effects in vivo, we initially used an acute pharmacological HF model (30 mg/kg per day isoproterenol, 7 days). Concurrent daily injections prevented HF and partially normalized cardiac morphology and GRK2 expression in this acute HF model. To investigate possible efficacy in halting progression of preexisting HF, calsequestrin cardiac transgenic mice (CSQ) with extant HF received daily injections for 28 days. The compound alone halted HF progression and partially normalized heart size, morphology, and cardiac expression of HF marker genes (GRK2, atrial natriuretic factor, and beta-myosin heavy chain).
conclusionsThese data suggest a promising therapeutic role for small molecule inhibition of pathological Gbetagamma signaling in the treatment of HF.
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