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Vol. 291, Issue 3, 1179-1187, December 1999
Department of Pharmacology and Toxicology, Michigan State
University, East Lansing, Michigan
5-Hydroxytryptamine (5-HT) activates the extracellular signal-regulated
kinase (Erk) mitogen-activated protein kinases (MAPKs) in the
vasculature, resulting in contraction. The mechanisms by which this
occurs are unclear. G protein-coupled receptors can activate Erk MAPK
pathways through a variety of mechanisms, including stimulation of Src,
phosphoinositide-3 kinase (PI-3-K), protein kinase C (PKC), or the
epidermal growth factor (EGF) receptor tyrosine kinase. We hypothesize
that 5-HT uses one or more of these pathways. In isolated strips of rat
aorta, the MAPK/Erk kinase inhibitor U0126 (50 µM), Src inhibitor PP1
(0.5 µM), PKC inhibitors calphostin C (1 µM) and chelerythrine (10 µM), and the PI-3-K inhibitor LY294002 (1-20 µM) reduced
5-HT-induced contraction. The EGF receptor tyrosine kinase inhibitor
AG1478 (0.25-1 µM) was without effect. Thus, 5-HT activates PKC,
Src, and possibly PI-3-K to result in contraction. In rat aortic
myocytes, 5-HT (1 µM) activated Erk MAPK proteins 2- to 3-fold over
basal values; activation was reduced by U0126, PP1, and LY294002 and
unaffected by calphostin C or chelerythrine, wortmannin, or AG1478. The
lack of effect of EGF receptor tyrosine kinase and PI-3-K inhibitors was confirmed in that the EGF receptor immunoprecipitated from 5-HT-exposed cells did not display an increase in autophosphorylation, nor did 5-HT significantly increase activation of Akt/protein kinase B,
a downstream substrate for PI-3-K. These data suggest that the rat
aortic 5-HT2A receptor uses Src but not PKC, PI-3-K, or the
EGF receptor tyrosine kinase in stimulating Erk MAPK activation.
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