ArticleThe Journal of clinical investigation2010
GSK-3alpha directly regulates beta-adrenergic signaling and the response of the heart to hemodynamic stress in mice.
Article in The Journal of clinical investigation, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 67 citations in OpenAlex.
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- Identification of Biomarkers for Right Ventricular Dysfunction in Idiopathic Dilated Cardiomyopathy Via Urinary Proteomics and Machine Learning.Journal of the American Heart Association · 2026Article
- GSK3α negatively regulates GSK3β by decreasing its protein levels and enzymatic activity in mouse embryonic stem cells.Stem cell reports · 2025Article
- Animal models of haploinsufficiency revealed the isoform-specific role of GSK-3 in HFD-induced obesity and glucose intolerance.American journal of physiology. Cell physiology · 2024Article
- Cardiac fibroblast GSK-3α aggravates ischemic cardiac injury by promoting fibrosis, inflammation, and impairing angiogenesis.Basic research in cardiology · 2023Article
- GSK-3 at the heart of cardiometabolic diseases: Isoform-specific targeting is critical to therapeutic benefit.Biochimica et biophysica acta. Molecular basis of disease · 2023Review
- Role of the Glycogen Synthase Kinase 3-Cyclic AMP/Protein Kinase A in the Immobilization of Human Sperm by Tideglusib.Reproductive sciences (Thousand Oaks, Calif.) · 2023Article
- Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation.Circulation research · 2023Article
- Cardiac natriuretic peptide deficiency sensitizes the heart to stress-induced ventricular arrhythmias via impaired CREB signalling.Cardiovascular research · 2022Article
- Beta 2 adrenergic receptor and mu opioid receptor interact to potentiate the aggressiveness of human breast cancer cell by activating the glycogen synthase kinase 3 signaling.Breast cancer research : BCR · 2022Article
- Glycogen synthase kinase GSK3α promotes tumorigenesis by activating HIF1/VEGFA signaling pathway in NSCLC tumor.Cell communication and signaling : CCS · 2022Article
- Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases.Medicinal research reviews · 2022Review
- Isoform-Specific Role of GSK-3 in High Fat Diet Induced Obesity and Glucose Intolerance.Cells · 2022Article
- GSK3α: An Important Paralog in Neurodegenerative Disorders and Cancer.Biomolecules · 2020Review
- β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD.JCI insight · 2020Article
- Mechanotransduction and Adrenergic Stimulation in Arrhythmogenic Cardiomyopathy: An Overview ofFrontiers in physiology · 2020Review
- Generation of Nppa-tagBFP reporter knock-in mouse line for studying cardiac chamber specification.Genesis (New York, N.Y. : 2000) · 2019Article
- Cardiomyocyte-GSK-3α promotes mPTP opening and heart failure in mice with chronic pressure overload.Journal of molecular and cellular cardiology · 2019Article
- The deubiquitinase ubiquitin-specific protease 20 is a positive modulator of myocardial βThe Journal of biological chemistry · 2019Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 2 countries.
Funding
Abstract
The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, alpha and beta. Although GSK-3beta has an important role in cardiac development, much remains unknown about the function of either GSK-3 isoform in the postnatal heart. Herein, we present what we believe to be the first studies defining the role of GSK-3alpha in the mouse heart using gene targeting. Gsk3a(-/-) mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile dysfunction. Following thoracic aortic constriction in young mice, we observed enhanced hypertrophy that rapidly transitioned to ventricular dilatation and contractile dysfunction. Surprisingly, markedly impaired beta-adrenergic responsiveness was found at both the organ and cellular level. This phenotype was reproduced by acute treatment of WT cardiomyocytes with a small molecule GSK-3 inhibitor, confirming that the response was not due to a chronic adaptation to LV dysfunction. Thus, GSK-3alpha appears to be the central regulator of a striking range of essential processes, including acute and direct positive regulation of beta-adrenergic responsiveness. In the absence of GSK-3alpha, the heart cannot respond effectively to hemodynamic stress and rapidly fails. Our findings identify what we believe to be a new paradigm of regulation of beta-adrenergic signaling and raise concerns given the rapid expansion of drug development targeting GSK-3.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.