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This Article Full Text Full Text (PDF) All Versions of this Article: 291/6/H2857    most recent 00229.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Ogden, K. Articles by Watts, S. W. Search for Related Content PubMed PubMed Citation Articles by Ogden, K. Articles by Watts, S. W.

A new signaling paradigm for serotonin: use of Crk-associated substrate in arterial contraction

¹Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan; and ²Center for Cardiovascular Sciences, Albany Medical College, Albany, New York

Submitted 5 March 2006 ; accepted in final form 19 July 2006

Crk-associated substrate (CAS), a 130-kDa adaptor protein, was discovered as a tyrosine kinase substrate of Src that was important to cellular motility and actin filament formation. As the tyrosine kinase Src is utilized by the 5-hydroxytryptamine (5-HT)_2A receptor in arterial contraction, we tested the hypothesis that CAS was integral to 5-HT_2A receptor-mediated vasoconstriction. Rat thoracic aorta was used as a model of the arterial 5-HT_2A receptor. Western and immunohistochemistry analyses validated the presence of CAS in the aorta, and tissue bath experiments demonstrated reduction of contraction to 5-HT (13.5 ± 5% control maximum) and the 5-HT₂ receptor agonist -methyl-5-HT (6 ± 2% maximum) by latrunculin B (10^–6 mol/l), an actin disruptor. In aorta contracted with 5-HT (10^–5 mol/l), tyrosine phosphorylation (Tyr410) of CAS was significantly increased (225%), and both contraction and CAS phosphorylation were reduced by the 5-HT_2A/2C receptor antagonist ketanserin (3 x 10^–8 mol/l). Src is one candidate for 5-HT-stimulated CAS tyrosyl-phosphorylation as 5-HT promoted interaction of Src and CAS in coimmunoprecipitation experiments, and the Src tyrosine kinase inhibitor PP1 (10^–5 mol/l) abolished 5-HT-induced tyrosyl-phosphorylation of CAS and reduced 5-HT- and -methyl-5-HT-induced contraction. Antisense oligodeoxynucleotides delivered to the aorta reduced CAS expression (33% control) and arterial contraction to -methyl-5-HT (45% of control), independent of changes in myosin light chain phosphorylation. These data are the first to implicate CAS in the signal transduction of 5-HT.

5-hydroxytryptamine; antisense oligodeoxynucleotides; signal transduction; Src

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