CaMKII negatively regulates calcineurin-NFAT signaling in cardiac myocytes
| Autor: | Steven R. Houser, Abdel Karim Sabri, Marie Hanscome, Joan Heller Brown, Remus M. Berretta, Hajime Kubo, Scott M. MacDonnell, Jeffery D. Molkentin, Jutta Weisser-Thomas, Naser Jaleel, Qinghang Liu, Xiongwen Chen |
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| Rok vydání: | 2009 |
| Předmět: |
NFATC3
medicine.medical_specialty Cytoplasm Physiology Heart Ventricles Active Transport Cell Nucleus Muscle Proteins Cardiomegaly Biology Article Rats Sprague-Dawley Calmodulin Internal medicine Ca2+/calmodulin-dependent protein kinase medicine Myocyte Animals Humans Myocytes Cardiac Phosphorylation CAMK Cell Nucleus NFATC Transcription Factors Caspase 3 Calcineurin NFAT Cell biology Rats Endocrinology Mutation cardiovascular system Cats Calcium Signal transduction Cardiology and Cardiovascular Medicine Calcium-Calmodulin-Dependent Protein Kinase Type 2 K562 Cells |
| Zdroj: | Circulation research. 105(4) |
| ISSN: | 1524-4571 |
| Popis: | Rationale: Pathological cardiac myocyte hypertrophy is thought to be induced by the persistent increases in intracellular Ca 2+ needed to maintain cardiac function when systolic wall stress is increased. Hypertrophic Ca 2+ binds to calmodulin (CaM) and activates the phosphatase calcineurin (Cn) and CaM kinase (CaMK)II. Cn dephosphorylates cytoplasmic NFAT (nuclear factor of activated T cells), inducing its translocation to the nucleus where it activates antiapoptotic and hypertrophic target genes. Cytoplasmic CaMKII regulates Ca 2+ handling proteins but whether or not it is directly involved in hypertrophic and survival signaling is not known. Objective: This study explored the hypothesis that cytoplasmic CaMKII reduces NFAT nuclear translocation by inhibiting the phosphatase activity of Cn. Methods and Results: Green fluorescent protein–tagged NFATc3 was used to determine the cellular location of NFAT in cultured neonatal rat ventricular myocytes (NRVMs) and adult feline ventricular myocytes. Constitutively active (CaMKII-CA) or dominant negative (CaMKII-DN) mutants of cytoplasmic targeted CaMKII δc were used to activate and inhibit cytoplasmic CaMKII activity. In NRVM CaMKII-DN (48.5±3%, P P 2+ increased Cn-dependent NFAT translocation (to 71.7±7%, P P Conclusion: These data show that activation of cytoplasmic CaMKII inhibits NFAT nuclear translocation by phosphorylation and subsequent inhibition of Cn. |
| Databáze: | OpenAIRE |
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