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Journal of Pharmacology and Experimental Therapeutics

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OtherCARDIOVASCULAR PHARMACOLOGY

Integration of Mitogen-Activated Protein Kinase Kinase Activation in Vascular 5-Hydroxytryptamine2A Receptor Signal Transduction

Jennifer A. Florian and Stephanie W. Watts
Journal of Pharmacology and Experimental Therapeutics January 1998, 284 (1) 346-355;
Jennifer A. Florian
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Stephanie W. Watts
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Abstract

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, α-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, α-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-HT2Areceptor 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-HT2Areceptors.

Footnotes

  • Send reprint requests to: Jennifer A. Florian, B445 Life Sciences Building, Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317. E-mail:wattss{at}pilot.msu.edu

  • ↵1 This work was supported by a grant from the American Heart Association, Michigan Affiliate.

  • ↵2 Written by Wayne Rasband at the National Institutes of Health and available from the Internet by anonymous ftp fromzippy.nimh.nih.gov or on floppy disk from NTIS, 5285 Port Royal Road, Springfield, VA 22161, part number PB93-504868.

  • ↵3 S. W. Watts, unpublished data.

  • Abbreviations:
    DMEM
    Dulbecco’s modified Eagle’s medium
    DOI
    2,5-dimethoxy-4-iodoamphetamine
    Erk
    extracellular signal-regulated kinase
    ANOVA
    analysis of variance
    GAP
    GTPase-activating factor
    GRF
    GTP-releasing factor
    5-HT
    5-hydroxytryptamine
    MAP
    mitogen-activated protein
    MAPK
    mitogen-activated protein kinase
    MEK
    mitogen-activated protein kinase kinase
    NCDC
    2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate
    PE
    phenylephrine
    PH
    pleckstrin homology
    PI3K
    phosphoinositide-3-kinase
    PKC
    protein kinase C
    PLC
    phospholipase C
    SDS
    sodium dodecyl sulfate
    SH
    src homology
    TBS
    Tris-buffered saline
    TBS-T
    Tris-buffered saline + Tween
    • Received July 23, 1997.
    • Accepted September 29, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 1
1 Jan 1998
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OtherCARDIOVASCULAR PHARMACOLOGY

Integration of Mitogen-Activated Protein Kinase Kinase Activation in Vascular 5-Hydroxytryptamine2A Receptor Signal Transduction

Jennifer A. Florian and Stephanie W. Watts
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 346-355;

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OtherCARDIOVASCULAR PHARMACOLOGY

Integration of Mitogen-Activated Protein Kinase Kinase Activation in Vascular 5-Hydroxytryptamine2A Receptor Signal Transduction

Jennifer A. Florian and Stephanie W. Watts
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 346-355;
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