Regulation of thromboxane receptor trafficking through the prostacyclin receptor in vascular smooth muscle cells: role of receptor heterodimerization.
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.


RESULTS
TPalpha 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 TPalpha 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, TPalpha was recycled to the cell surface in coexpressing HEK293 cells, but not in ASMCs, in accord with the postendocytotic pathway of IP.


CONCLUSIONS
IP/TPalpha interaction permits reciprocal regulation of receptor endocytosis via the trafficking pathway determined by the activated dimeric partner.
Wilson
Stephen J
SJ
Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
Dowling
Jennifer K
JK
Zhao
Lei
L
Carnish
Erin
E
Smyth
Emer M
EM
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002460:Cell Line; D002478:Cells, Cultured; D019281:Dimerization; D004705:Endocytosis / Q000502:physiology; D011464:Epoprostenol / Q000502:physiology; D005231:Fatty Acids, Unsaturated; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D016285:Iloprost / Q000494:pharmacology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D044006:Receptors, Epoprostenol / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013928:Thromboxane A2 / Q000502:physiology; D014162:Transfection
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D044006:Receptors, Epoprostenol; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2; C045749:SQ 29548; D011464:Epoprostenol; D016285:Iloprost