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PMID:20516643

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Citation

Zhou, J, Lal, H, Chen, X, Shang, X, Song, J, Li, Y, Kerkela, R, Doble, BW, MacAulay, K, DeCaul, M, Koch, WJ, Farber, J, Woodgett, J, Gao, E and Force, T (2010) GSK-3alpha directly regulates beta-adrenergic signaling and the response of the heart to hemodynamic stress in mice. J. Clin. Invest. 120:2280-91

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.

Links

PubMed PMC2898595 Online version:10.1172/JCI41407

Keywords

Adrenergic Agents; Animals; Cardiomegaly/genetics; Glycogen Synthase Kinase 3/genetics; Glycogen Synthase Kinase 3/metabolism; Glycogen Synthase Kinase 3/physiology; Heart/growth & development; Hemodynamics/genetics; Hypertrophy/genetics; Mice; Mice, Knockout; Myocytes, Cardiac/metabolism; Norepinephrine/genetics; Protein Isoforms/genetics; Protein-Serine-Threonine Kinases/genetics; Signal Transduction/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:GSK3A

involved_in

GO:2000467: positive regulation of glycogen (starch) synthase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GSK3A

involved_in

GO:0071879: positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GSK3A

involved_in

GO:0061052: negative regulation of cell growth involved in cardiac muscle cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GSK3A

involved_in

GO:0045823: positive regulation of heart contraction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GSK3A

involved_in

GO:0032007: negative regulation of TOR signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GSK3A

involved_in

GO:0106071: positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GSK3A

involved_in

GO:0003214: cardiac left ventricle morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GSK3A

involved_in

GO:0003073: regulation of systemic arterial blood pressure

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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