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Vol. 284, Issue 1, 346-355, 1998
Department of Pharmacology and Toxicology, Michigan State
University, East Lansing, Michigan
Vascular 5-Hydroxytryptamine2A (5-HT2A)
receptor signaling and contraction has been associated with the
activation of L-type calcium channels, phospholipase C (PLC) and, as we
previously demonstrated, tyrosine kinase activation. We hypothesize the
5-HT2A receptor activates all three pathways independently
to elicit contraction and that one of the tyrosine kinases activated by 5-HT is mitogen-activated protein kinase kinase (MEK).
Endothelium-denuded rat thoracic aorta was mounted into isolated tissue
baths for measurement of isometric contractile force. 5-HT,
-methyl-5-HT and 2,5-dimethoxy-4-iodoamphetamine all contracted the
rat aorta, whereas the 5-HT2A receptor antagonist
ketanserin (30 nM) blocked contraction to 5-HT. The tyrosine kinase
inhibitor genistein (5 µM) shifted contraction to 5-HT,
-methyl-5-HT and DOI ~10-fold to the right, whereas daidzein (5 µM), the inactive isomer of genistein, was unable to shift
5-HT-induced contraction. PD098059 (10 µM), an inhibitor of MEK,
shifted contraction to 5-HT ~7-fold to the right. We next examined
the integration of tyrosine kinase activation in 5-HT2A
receptor signaling. 5-HT-induced contraction was reduced individually
by the PLC inhibitor 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (NCDC; 100 µM) or the Ca++ channel inhibitor nifedipine
(50 nM); the remaining response to 5-HT was reduced by further addition
of either genistein or PD098059. When nifedipine and NCDC were used in
combination, a part of the contraction to 5-HT remained; this
contraction was further reduced by genistein or PD098059. In cultured
aortic smooth muscle cells, 5-HT (0.01-100 µM) stimulated
tyrosyl-phosphorylation of 42- and 44-kDa proteins identified as Erk
MAPKs; this phosphorylation was reduced by PD098059 (10 µM). Neither
nifedipine nor NCDC reduced 5-HT (1 µM)-stimulated Erk MAPK
tyrosyl-phosphorylation, but the combination of nifedipine, NCDC and
PD098059 abolished 5-HT (1 µM)-stimulated Erk MAPK
tyrosyl-phosphorylation. Taken together, these studies indicate that
stimulation of a vascular 5-HT2A receptor activates
Ca++ channels and PLC as well as MEK to cause rat aortic
contraction and that MEK activation is at least partially independent
of the two pathways classically associated with 5-HT2A
receptors.
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