The Raf-MEK-ERK cascade represents a common pathway for alteration of intracellular calcium by Ras and protein kinase C in cardiac myocytes

Peter D. Ho, Dietmar K. Zechner, Huaping He, Wolfgang H. Dillmann, Christopher C. Glembotski, Patrick M. McDonough

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)21730-21735
Number of pages6
JournalJournal of Biological Chemistry
Volume273
Issue number34
DOIs
StatePublished - Aug 21 1998
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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