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

Heterodimerization of the α and β isoforms of the human thromboxane receptor enhances isoprostane signaling

“…GPCR heterodimerization results frequently in substantial modifications of receptor function [10]. Indeed, we demonstrated previously that heterodimerization of TPα with the human receptor for prostacyclin (the IP) dramatically altered TP signaling [11]. More recently, TPα and TPβ were shown to heterodimerize with consequent alterations in receptor regulation and signaling in response to a TxA 2 analog [12,13].…”

“…Generation of HAhTPα was as described previously [11]. To generate MychTPβ, 5′-oligonucleotides which contained 3 miscellaneous bases, 6 bases encoding a HindIII site, the 3 bases immediately 5′ of the initiator methionine, 3 bases encoding a methionine, the epitope tag coding sequence and 21 bases encoding amino acids 2-8 were generated.…”

“…HEK293 cells (American Type Tissue Culture Collection, Rockville, MD) were maintained, and stably transfected with Myc-tagged TPβ or HA-tagged TPα, as previously described [11]. For transient transfections 50-80% confluent HEK293 were transfected using Fugene 6 (Roche Biochemicals, IN) according to the manufacturers instructions.…”

Light on the structure of thromboxane A2 receptor heterodimers

“…The functional role of such supra-molecular complexes is still unclear and may vary depending on the GPCR type [18,20]. In particular, for TP, the formation of TPa-TPb and TPa-IP heterodimers in constitutive human systems seems to greatly influence their pharmacological profiles [4][5][6], whereas no data are yet available on the functional significance of TP homodimerization. On the same line, the molecular architecture of either homodimers or heterodimers of TP is still obscure.…”

“…Emerging evidence suggests that many GPCRs exist as homo-and/or hetero-assemblies of two or more monomers [2,3]. The thromboxane A 2 receptor (TP) is not an exception, as in vitro evidence has shown that the a and b isoforms of this GPCR form homodimers and heterodimers independently from their functional state (this study and the papers from [4,5], as well as heterodimers with other prostanoid GPCRs [6,7]. Owing to the key roles played by TP for maintaining cardiovascular homeostasis as well as for its involvement in major cardiovascular events, such as myocardial infarction, thrombosis, and altered vessel wall reactivity [8], it is essential to shed some light on the role of dimerization/oligomerization in the functioning and regulation of this receptor.…”