on November 16, 2006
Published online before print November 16, 2006, doi: 10.1161/01.ATV.0000252667.53790.4e
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Submitted on November 30, 2005
Accepted on October 31, 2006
Regulation of Thromboxane Receptor Trafficking Through the Prostacyclin Receptor in Vascular Smooth Muscle Cells. Role of Receptor Heterodimerization
Stephen J. Wilson ;
From the Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia.
* To whom correspondence should be addressed. 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, after 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.
Key words: prostacyclin • thromboxane • G protein-coupled receptor • heterodimer • internalization
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