Biased suppression of TP homodimerization and signaling through disruption of a TM GxxxGxxxL helical interaction motif.

ABSTRACT: Thromboxane A2 (TXA2) contributes to cardiovascular disease (CVD) by activating platelets and vascular constriction and proliferation. Despite their preclinical efficacy, pharmacological antagonists of the TXA2 receptor (TP), a G protein-coupled receptor, have not been clinically successful, raising interest in novel approaches to modifying TP function. We determined that disruption of a GxxxGxxxL helical interaction motif in the human TP's (? isoform) fifth transmembrane (TM) domain suppressed TP agonist-induced Gq signaling and TP? homodimerization, but not its cell surface expression, ligand affinity, or Gq association. Heterodimerization of TP? with the functionally opposing prostacyclin receptor (IP) shifts TP? to signal via the IP-Gs cascade contributing to prostacyclin's restraint of TXA2 function. Interestingly, disruption of the TP?-TM5 GxxxGxxxL motif did not modify either IP-TP? heterodimerization or its Gs-cAMP signaling. Our study indicates that distinct regions of the TP? receptor direct its homo- and heterodimerization and that homodimerization is necessary for normal TP?-Gq activation. Targeting the TP?-TM5 GxxxGxxxL domain may allow development of biased TP? homodimer antagonists that avoid suppression of IP-TP? heterodimer function. Such novel therapeutics may prove superior in CVD compared with nonselective suppression of all TP functions with TXA2 biosynthesis inhibitors or TP antagonists.

SUBMITTER: Frey AJ 

PROVIDER: S-EPMC3646468 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature