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Am J Physiol Heart Circ Physiol (July 21, 2006). doi:10.1152/ajpheart.00229.2006
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Submitted on March 5, 2006
Accepted on July 19, 2006

A New Signaling Paradigm for Serotonin: Use of Crk-Associated Substrate in Arterial Contraction

Kevin Ogden1, Janice M Thompson1, Zachary Hickner1, Taoying Huang2, Dale D. Tang2, and Stephanie W. Watts1*

1 Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, United States
2 Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, United States

* To whom correspondence should be addressed. E-mail: wattss{at}msu.edu.

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-HT2A receptor in arterial contraction, we tested the hypothesis that CAS was integral to 5-HT2A receptor-mediated vasoconstriction. Rat thoracic aorta was used as a model of the arterial 5-HT2A 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 {alpha}-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 (Tyr 410) of CAS was significantly increased (~225%) and both contraction and CAS phosphorylation were reduced by the 5-HT2A/2C receptor antagonist ketanserin (3x10-8 mol/L). Src is one candidate for 5-HT-stimulated CAS tyrosyl-phosphorylation as 5-HT promoted interaction of Src and CAS in co-immunoprecipitation 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 {alpha}-methyl-5-HT-induced contraction. Antisense oligodeoxynucleotides delivered to the aorta reduced CAS expression (33% control) and arterial contraction to {alpha}-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.




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