Receptors coupled to the G(q) and G(12) 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 G(13) (of the G(12) family) by the thromboxane A(2) receptor alpha (TPalpha), via agonist-effected [(35)S]-guanosine 5'-O-(3-thio)triphosphate binding when the G proteins themselves are used as reporters. We find for TPalpha introduced into human embryonic kidney 293 cells and for the receptor expressed normally in human platelets an agonist-selective engagement of G(q) versus G(13). Pinane thromboxane A(2) (PTA(2)) activates G(q) in preference to G(13), whereas 8-iso-prostaglandin F(2alpha) activates G(13) in preference to G(q). 9,11-Dideoxy-9alpha,11alpha-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U46619), 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 PTA(2) is right-shifted from binding of the ligand to receptor, a manifestation of which is a bimodal action: PTA(2) is an antagonist at low concentrations and an agonist at higher concentrations. We posit two populations of TPalpha, 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.