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Research ArticleArticle

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

Li Zhang, Lawrence F. Brass and David R. Manning
Molecular Pharmacology January 2009, 75 (1) 235-241; DOI: https://doi.org/10.1124/mol.108.050906
Li Zhang
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Lawrence F. Brass
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David R. Manning
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Abstract

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.

Footnotes

  • This work was supported by National Institutes of Health grant GM066892.

  • ABBREVIATIONS: GTPγS, guanosine 5′-O-(3-thio)triphosphate; TXA2, thromboxane A2; U46619, 9,11-dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid; SQ29548, [1S-[1α,2α(Z),3α,4α]]-7-[3-[[2-[(phenyl amino)carbonyl]hydrazine]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; PTA2, pinane-thromboxane A2; 8-iso-PGF2α, 8-iso-prostaglandin F2α; HEK, human embryonic kidney; TP, receptor(s) for thromboxane A2; CGP12177, 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one.

    • Received July 29, 2008.
    • Accepted October 24, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (1)
Molecular Pharmacology
Vol. 75, Issue 1
1 Jan 2009
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Research ArticleArticle

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

Li Zhang, Lawrence F. Brass and David R. Manning
Molecular Pharmacology January 1, 2009, 75 (1) 235-241; DOI: https://doi.org/10.1124/mol.108.050906

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Research ArticleArticle

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

Li Zhang, Lawrence F. Brass and David R. Manning
Molecular Pharmacology January 1, 2009, 75 (1) 235-241; DOI: https://doi.org/10.1124/mol.108.050906
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