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J Biol Chem, Vol. 274, Issue 14, 9760-9770, April 2, 1999

Both G_s and G_i Proteins Are Critically Involved in Isoproterenol-induced Cardiomyocyte Hypertrophy

Yunzeng Zou, Issei Komuro, Tsutomu Yamazaki, Sumiyo Kudoh, Hiroki Uozumi, Takashi Kadowaki, and Yoshio Yazaki

From the  Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113 8655, and the  Health Service Center, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Activation of -adrenoreceptors induces cardiomyocyte hypertrophy. In the present study, we examined isoproterenol-evoked intracellular signal transduction pathways leading to activation of extracellular signal-regulated kinases (ERKs) and cardiomyocyte hypertrophy. Inhibitors for cAMP and protein kinase A (PKA) abolished isoproterenol-evoked ERK activation, suggesting that G_s protein is involved in the activation. Inhibition of G_i protein by pertussis toxin, however, also suppressed isoproterenol-induced ERK activation. Overexpression of the G subunit binding domain of the -adrenoreceptor kinase 1 and of COOH-terminal Src kinase, which inhibit functions of G and the Src family tyrosine kinases, respectively, also inhibited isoproterenol-induced ERK activation. Overexpression of dominant-negative mutants of Ras and Raf-1 kinase and of the -adrenoreceptor mutant that lacks phosphorylation sites by PKA abolished isoproterenol-stimulated ERK activation. The isoproterenol-induced increase in protein synthesis was also suppressed by inhibitors for PKA, G_i, tyrosine kinases, or Ras. These results suggest that isoproterenol induces ERK activation and cardiomyocyte hypertrophy through two different G proteins, G_s and G_i. cAMP-dependent PKA activation through G_s may phosphorylate the -adrenoreceptor, leading to coupling of the receptor from G_s to G_i. Activation of G_i activates ERKs through G, Src family tyrosine kinases, Ras, and Raf-1 kinase.

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