文章基本信息

标题：Biased suppression of TP homodimerization and signaling through disruption of a TM GxxxGxxxL helical interaction motif
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作者：Alexander J. Frey ; Salam Ibrahim ; Scott Gleim 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2013
卷号：54
期号：6
页码：1678-1690
DOI：10.1194/jlr.M036673
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：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 of TXA₂ function. Interestingly, disruption of the TPα-TM5 GxxxGxxxL motif did not modify either IP-TPα heterodimerization or its Gs-cAMP signaling. Our study indicates that distinct regions of the TPα receptor direct its homo- and heterodimerization and that homodimerization is necessary for normal TPα-Gq activation. Targeting the TPα-TM5 GxxxGxxxL domain may allow development of biased TPα homodimer antagonists that avoid suppression of IP-TPα 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.
关键词：G protein-coupled receptor ; dimerization ; transmembrane ; transmembrane domain ; biased antagonism ; thromboxane A₂ receptor