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J. Biol. Chem., Vol. 279, Issue 51, 53036-53047, December 17, 2004

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Dimerization of the Human Receptors for Prostacyclin and Thromboxane Facilitates Thromboxane Receptor-mediated cAMP Generation^*

Stephen J. Wilson, Aoife M. Roche, Ekaterina Kostetskaia, and Emer M. Smyth

From the Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Prostacyclin (PGI₂) and thromboxane (TxA₂) are biological opposites; PGI₂, a vasodilator and inhibitor of platelet aggregation, limits the deleterious actions of TxA₂, a vasoconstrictor and platelet activator. The molecular mechanisms involved in the counterregulation of PGI₂/TxA₂ signaling are unclear. We examined the interaction of the receptors for PGI₂ (IP) and TxA₂ (TP). IP-induced cAMP and TP-induced inositol phosphate generation were unaltered when the receptors were co-expressed in HEK 293 cells (IP/TP-HEK). TP-cAMP generation, in response to TP agonists or a TP-dependent isoprostane, iPE₂III, was evident in IP/TP-HEK and in aortic smooth muscle cells, but not in cells expressing either receptor alone, or in IP-deficient aortic smooth muscle cells. Augmentation of TP-induced cAMP generation, with the IP agonist cicaprost, was ablated in IP-deficient cells and was independent of direct IP signaling. IP/TP heterodimers were formed constitutively when the receptors were co-expressed, with no overt changes in ligand binding to the individual receptor sites. However, despite inefficient binding of iPE₂III to either the IP or TP, expressed alone or in combination, robust cAMP generation was evident in IP/TP-HEK, suggesting the formation of an alternative receptor site. Thus, IP/TP dimerization was coincident with TP-cAMP generation, promoting a "PGI₂-like" cellular response to TP activation. This represents a previously unknown mechanism by which IP may limit the cellular effects of TP.

Received for publication, May 5, 2004 , and in revised form, September 13, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Center for Experimental Therapeutics, University of Pennsylvania, 808 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-573-2323; Fax: 215-573-9004; E-mail: emer{at}spirit.gcrc.upenn.edu.

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