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The G₁₂ Family of G Proteins as a Reporter of Thromboxane A₂ Receptor Activity

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Despite advances in the understanding of pathways regulated by the G₁₂ family of heterotrimeric G proteins, much regarding the engagement of this family by receptors remains unclear. We explore here, using the thromboxane A₂ receptor TP, the ability of G₁₂ and G₁₃ to report differences in the potency and efficacy of receptor ligands. We were interested especially in the potential of the isoprostane 8-iso-prostaglandin F (8-iso-PGF₂), among other ligands examined, to activate G₁₂ and G₁₃ through TP explicitly. We were also interested in the functionality of TP-G fusion proteins germane to G₁₂ and G₁₃. Using fusion proteins in Spodoptera frugiperda (Sf9) cells and independently expressed proteins in human embryonic kidney 293 cells, and using guanosine 5'-O-(3-[³⁵S]thio)triphosphate binding to evaluate G activation directly, we found for G that no ligand tested, including 8-iso-prostaglandin F (8-iso-PGF₂ and a purported antagonist (pinane thromboxane A₂), was silent. The activity of agonists was especially pronounced when evaluated for TP-G₁₃ and in the context of receptor reserve. Agonist activity for 8-iso-PGF₂ was diminished and that for pinane thromboxane A nonexistent when G₁₂ was the reporter. These data establish that G₁₂ and G₁₃ can report differentially potency and efficacy and underscore the relevance of receptor and G protein context.

Address correspondence to: Dr. David R. Manning, Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104-6084. E-mail: manning{at}pharm.med.upenn.edu

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