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Vol. 55, Issue 2, 296-303, February 1999
Department of Pharmacology, Emory University School of Medicine,
Atlanta, Georgia
We studied the role of Ca++ and protein kinase C (PKC) in
alpha-1A adrenergic receptor (AR)-mediated activation of
mitogen-activated protein kinase pathways in PC12 cells. In PC12 cells
stably transfected with the human alpha-1A AR,
norepinephrine (NE) strongly activated both extracellular signal
regulated kinases (ERKs) and c-jun-NH2-terminal kinases
(JNK). Ten nanomolar thapsigargin (TG) increased cytoplasmic Ca++ at least as much as NE but did not activate ERKs or
JNK. Higher concentrations of TG caused a small activation of ERKs but
not JNK. Emptying [Ca++]i stores by
pretreatment with TG prevented the NE-stimulated increase in
[Ca++]i but not ERK or JNK activation. The
Ca++ chelator
bis(2-aminophenoxy)ethane-N-N-N'-N'-tetraacetate (BAPTA) dose dependently abolished NE-stimulated Ca++ responses but
not ERK or JNK activation. NE increased tyrosine phosphorylation of
Pyk2, and this response was neither blocked by BAPTA nor mimicked by
TG. The phorbol ester tumor promoting agent (TPA) caused a
dose-dependent activation of ERKs that was potentiated by 10 nM TG. TPA
caused only a small activation of JNK relative to that caused by NE,
which was not affected by TG. The potent PKC inhibitor
bisindolylmaleimide I dose dependently inhibited ERK and JNK activation
by TPA, but not NE. ATP and UTP activated similar mitogen-activated
protein kinase responses through endogenous P2Y2 receptors, and these
responses were not blocked by BAPTA or bisindolylmaleimide I,
suggesting that these results may be generalizable to other
Gq/11-coupled receptors. The results suggest that
Ca++ release and PKC activation are neither necessary nor
sufficient for alpha-1A AR-mediated activation of
mitogenic responses in PC12 cells.
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