© 1996 American Heart Association, Inc.
Articles |
Endothelin-Dependent Actions in Cultured AT-1 Cardiac Myocytes
The Role of the 
Isoform of Protein Kinase C
From the Departments of Medicine (S.F.S.) and Pharmacology (T.J., E.P., H.Z., R.P.K., S.F.S.), Columbia University, New York, NY.
Correspondence to Susan F. Steinberg, MD, Associate Professor of Medicine and Pharmacology, Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 W 168 St, New York, NY 10032.
Abstract The consequences of endothelin receptor activation
were examined in atrial tumor myocytes derived from transgenic mice
(AT-1 cells). Endothelin-1 (endothelin) stimulates
phosphoinositide hydrolysis in a dose-dependent
manner. Endothelin also induces the rapid and transient translocation
of protein kinase C (PKC)-
immunoreactivity from the soluble to the
particulate cell fraction. The subcellular distributions of PKC
and
PKC
(also expressed by AT-1 cells) are not influenced by endothelin.
Using quantitative fluorescence microscopy with fura 2, we
examined the effects of endothelin on intracellular calcium. In
electrically driven myocytes, endothelin induces a rapid and transient
increase in the amplitude of the calcium transient. This is blocked by
both phorbol 12-myristate 13-acetate (PMA) pretreatment to
downregulate PKC and the PKC inhibitor chelerythrine,
arguing that PKC plays a critical role in endothelin
receptor–dependent increases in intracellular calcium. Endothelin
also stimulates mitogen-activated protein kinase (MAPK).
MAPK activation is markedly attenuated by pretreatment with PMA or
pertussis toxin (PTX, to inactivate susceptible G protein
subunits); it is completely prevented by combined pretreatment with
PMA and PTX. In contrast, it is not attenuated by chelation of
intracellular calcium with BAPTA. These findings indicate that the
pathway for endothelin receptor stimulation of MAPK involves PKC and
PTX-sensitive G protein(s). Thus, these studies identify a functional
role for PKC as a mediator of endothelin receptor–dependent
increases in cytosolic calcium and MAPK activity in AT-1 cells.
Accordingly, the AT-1 cell system should provide a uniquely useful
model to identify the intracellular targets for PKC and investigate
their function in the regulation of intracellular calcium homeostasis
and the induction of the growth response in cardiac myocytes.
Key Words: endothelin • protein kinase C • G proteins • mitogen-activated protein kinase • Ca2+
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