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J Biol Chem, Vol. 273, Issue 34, 21730-21735, August 21, 1998

The Raf-MEK-ERK Cascade Represents a Common Pathway for Alteration of Intracellular Calcium by Ras and Protein Kinase C in Cardiac Myocytes

From the Department of Biology and the Molecular Biology Institute, San Diego State University, San Diego, California 92182

Ras and protein kinase C (PKC), which regulate the Raf-MEK-ERK cascade, may participate in the development of cardiac hypertrophy, a condition characterized by diminished and prolonged contractile calcium transients. To directly examine the influence of this pathway on intracellular calcium ([Ca²⁺]_i), cardiac myocytes were cotransfected with effectors of this pathway and with green fluorescent protein, which allowed the living transfected myocytes to be identified and examined for [Ca²⁺]_i via indo-1. Transfection with constitutively active Ras (Ha-Ras^V12) increased cell size, decreased expression of the myofibrils and the calcium-regulatory enzyme SERCA2, and reduced the magnitude and prolonged the decay phase of the contractile [Ca²⁺]_i transients. Similar effects on [Ca²⁺]_i were obtained with Ha-Ras^V12S35, a Ras mutant that selectively couples to Raf, and with constitutively active Raf. In contrast, Ha-Ras^V12C40, a Ras mutant that activates the phosphatidylinositol 3-kinase pathway, had a lesser effect. The PKC-activating phorbol ester, phorbol 12-myristate 13-acetate, also prolonged the contractile [Ca²⁺]_i transients. Cotransfection with dnMEK inhibited the effects of Ha-Ras^V12, Raf, and phorbol 12-myristate 13-acetate on [Ca²⁺]_i. The effects of Ha-Ras^V12 and Raf on [Ca²⁺]_i were also counteracted by SERCA2 overexpression. Both Ras and PKC may thus regulate cardiac [Ca²⁺]_i via the Raf-MEK-ERK cascade, and this pathway may represent a critical determinant of cardiac physiological function.

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