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 (α isoform) fifth transmembrane (TM) domain suppressed TP agonist-induced Gq signaling and TPα homodimerization, but not its cell surface expression, ligand affinity, or Gq association. Heterodimerization of TPα with the functionally opposing prostacyclin receptor (IP) shifts TPα to signal via the IP-Gs cascade contributing to prostacyclin's restraint o

SUBMITTER: Frey AJ 

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

REPOSITORIES: biostudies-literature