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(Circulation. 2001;104:102.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Isoproterenol Activates Extracellular Signal–Regulated Protein Kinases in Cardiomyocytes Through Calcineurin

Yunzeng Zou, MD, PhD; Atsushi Yao, MD, PhD; Weidong Zhu, MD; Sumiyo Kudoh, MD, PhD; Yukio Hiroi, MD, PhD; Masaki Shimoyama, MD, PhD; Hiroki Uozumi, MD; Osami Kohmoto, MD, PhD; Toshiyuki Takahashi, MD, PhD; Futoshi Shibasaki, MD, PhD; Ryozo Nagai, MD, PhD; Yoshio Yazaki, MD, PhD; Issei Komuro, MD, PhD

From the Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba (Y.Z., I.K.); Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo (A.Y., W.Z., S.K., Y.H., M.S., H.U., T.T., R.N., Y.Y.); Department of Medicine II, Saitama Medical School, Saitama (O.K.); and Tokyo Metropolitan Institute of Medical Science, Tokyo (F.S.), Japan.

Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail komuro-tky{at}umin.ac.jp

Background—Extracellular signal–regulated kinases (ERKs) and calcineurin have been reported to play important roles in the development of cardiac hypertrophy. We examined here the relation between calcineurin and ERKs in cardiomyocytes.

Methods and Results—Isoproterenol activated ERKs in cultured cardiomyocytes of neonatal rats, and the activation was abolished by chelation of extracellular Ca²⁺ with EGTA, blockade of L-type Ca²⁺ channels with nifedipine, or depletion of intracellular Ca²⁺ stores with thapsigargin. Isoproterenol-induced activation of ERKs was also significantly suppressed by calcineurin inhibitors in cultured cardiomyocytes as well as in the hearts of mice. Isoproterenol failed to activate ERKs in either the cultured cardiomyocytes or the hearts of mice that overexpress the dominant negative mutant of calcineurin. Isoproterenol elevated intracellular Ca²⁺ levels at both systolic and diastolic phases and dose-dependently activated calcineurin. Inhibition of calcineurin also attenuated isoproterenol-stimulated phosphorylation of Src, Shc, and Raf-1 kinase. The immunocytochemistry revealed that calcineurin was localized in the Z band, and isoproterenol induced translocation of calcineurin and ERKs into the nucleus.

Conclusions—Calcineurin, which is activated by marked elevation of intracellular Ca²⁺ levels by the Ca²⁺-induced Ca²⁺ release mechanism, regulates isoproterenol-induced activation of ERKs in cardiomyocytes.

Key Words: calcium • calcineurin • myocytes • kinases • isoproterenol

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