RT Journal Article
SR Electronic
T1 The Gq and G12 Families of Heterotrimeric G Proteins Report Functional Selectivity
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 235
OP 241
DO 10.1124/mol.108.050906
VO 75
IS 1
A1 Li Zhang
A1 Lawrence F. Brass
A1 David R. Manning
YR 2009
UL http://molpharm.aspetjournals.org/content/75/1/235.abstract
AB Receptors coupled to the Gq 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 Gq and G13 (of the G12 family) by the thromboxane A2 receptor α (TPα), via agonist-effected [35S]-guanosine 5′-O-(3-thio)triphosphate binding when the G proteins themselves are used as reporters. We find for TPα introduced into human embryonic kidney 293 cells and for the receptor expressed normally in human platelets an agonist-selective engagement of Gq versus G13. Pinane thromboxane A2 (PTA2) activates Gq in preference to G13, whereas 8-iso-prostaglandin F2α activates G13 in preference to Gq. 9,11-Dideoxy-9α,11α-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 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 TPα, 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. The American Society for Pharmacology and Experimental Therapeutics