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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:290.)
© 2007 American Heart Association, Inc.

Vascular Biology

Regulation of Thromboxane Receptor Trafficking Through the Prostacyclin Receptor in Vascular Smooth Muscle Cells

Role of Receptor Heterodimerization

Stephen J. Wilson; Jennifer K. Dowling; Lei Zhao; Erin Carnish; Emer M. Smyth

From the Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia.

Correspondence to Dr Emer M Smyth, Institute of Translational Medicine and Therapeutics, University of Pennsylvania, 808 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104. E-mail emer{at}spirit.gcrc.upenn.edu

Background— Prostacyclin (PGI₂) and thromboxane (TxA₂) effect disparate outcomes for atherogenesis and the response to vascular injury; PGI₂, a vasodilator and inhibitor of platelet aggregation, limits the deleterious actions of TxA₂, a vasoconstrictor and platelet activator. Dimerization of their G protein-coupled receptors, IP and TP, evokes a modified cellular response through which IP/TP counter-balance may be effected. We examined the consequence of IP/TP interaction for the regulatory pathways of both receptors.

Methods and Results— TP overexpressed in HEK293 cells or expressed endogenously in aortic smooth muscle cells (ASMCs) was internalized after selective activation of either TP or IP. Homologous trafficking of TP was unaltered by coexpression of IP. Heterologous sequestration of TP required the physical presence of activated IP, in transfected and native cells, but was independent of IP signaling to adenylyl cyclase. Reciprocal heterologous regulation of IP, via activated TP, was evident in both HEK293 cells and ASMCs. Homologous TP internalization led to receptor retention and degradation. In contrast, when internalization was IP-induced, TP was recycled to the cell surface in coexpressing HEK293 cells, but not in ASMCs, in accord with the postendocytotic pathway of IP.

Conclusions— IP/TP interaction permits reciprocal regulation of receptor endocytosis via the trafficking pathway determined by the activated dimeric partner.

Interaction of the G protein-coupled receptors for prostacyclin (IP) and thromboxane (TP) permits reciprocal regulation of receptor endocytosis via a trafficking pathway determined by the activated dimeric partner. This represents a further mechanism by which dimerization may effect the IP-TP counterbalance.

Key Words: prostacyclin • thromboxane • G protein-coupled receptor • heterodimer • internalization

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