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J Biol Chem, Vol. 273, Issue 34, 21730-21735, August 21, 1998
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-RasV12) 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-RasV12S35, a Ras mutant that selectively couples to Raf,
and with constitutively active Raf. In contrast,
Ha-RasV12C40, 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-RasV12, Raf, and phorbol 12-myristate 13-acetate on
[Ca2+]i. The effects of Ha-RasV12 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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