Endothelin-1-Stimulated InsP₃-Induced Ca²⁺ Release Is a Nexus for Hypertrophic Signaling in Cardiac Myocytes

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• 作者：Daniel R. Higazi ; Claire J. Fearnley ; Faye M. Drawnel ; Amarnath Talasila ; Elaine M. Corps ; Oliver Ritter ; Fraser McDonald ; Katsuhiko Mikoshiba ; Martin D. Bootman ; H. Llewelyn Roderick
• 刊名：Molecular Cell
• 出版年：2009
• 出版时间：27 February 2009
• 年：2009
• 卷：33
• 期：4
• 页码：472-482
• 全文大小：1020 K

文摘

Summary

Ca²⁺ elevations are fundamental to cardiac physiology-stimulating contraction and regulating the gene transcription that underlies hypertrophy. How Ca²⁺ specifically controls gene transcription on the background of the rhythmic Ca²⁺ increases required for contraction is not fully understood. Here we identify a hypertrophy-signaling module in cardiac myocytes that explains how Ca²⁺ discretely regulates myocyte hypertrophy and contraction. We show that endothelin-1 (ET-1) stimulates InsP₃-induced Ca²⁺ release (IICR) from perinuclear InsP₃Rs, causing an elevation in nuclear Ca²⁺. Significantly, we show that IICR, but not global Ca²⁺ elevations associated with myocyte contraction, couple to the calcineurin (CnA)/NFAT pathway to induce hypertrophy. Moreover, we found that activation of the CnA/NFAT pathway and hypertrophy by isoproterenol and BayK8644, which enhance global Ca²⁺ fluxes, was also dependent on IICR and nuclear Ca²⁺ elevations. The activation of IICR by these activity-enhancing mediators was explained by their ability to stimulate secretion of autocrine/paracrine ET-1.