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The G_q and G₁₂ Families of Heterotrimeric G Proteins Report Functional Selectivity

From the Departments of Pharmacology (L.Z., D.R.M.) and Medicine (L.F.B.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Receptors coupled to the G_q and G₁₂ families of heterotrimeric G proteins have surfaced rarely in the context of functional selectivity and always indirectly. We explore here the differential engagement of G_q and G₁₃ (of the G₁₂ family) by the thromboxane A₂ receptor (TP), via agonist-effected [³⁵S]-guanosine 5'-O-(3-thio)triphosphate binding when the G proteins themselves are used as reporters. We find for TP introduced into human embryonic kidney 293 cells and for the receptor expressed normally in human platelets an agonist-selective engagement of G_q versus G₁₃. Pinane thromboxane A₂ (PTA₂) activates G_q in preference to G₁₃, whereas 8-iso-prostaglandin F₂ activates G₁₃ in preference to G_q. 9,11-Dideoxy-9,11-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U46619 [GenBank] ), in contrast, exhibits no preference. Reserve of receptor in relation to G protein and of G protein in relation to downstream events is apparent in some instances but does not have a bearing on selectivity. Activation of G proteins by PTA₂ is right-shifted from binding of the ligand to receptor, a manifestation of which is a bimodal action: PTA₂ is an antagonist at low concentrations and an agonist at higher concentrations. We posit two populations of TP, or two intrinsic sites of ligand binding, with selectivity evident not only in terms of the G proteins activated but properties of antagonism versus agonism.

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