Crosstalk between Gαi- and Gαq-coupled receptors is mediated by Gβγ exchange

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 19; pp. 10626 - 10631
• Main Authors: Quitterer, Ursula, Lohse, Martin J.
• Format: Journal Article
• Language: English
• Published: National Acad Sciences 14-09-1999; National Academy of Sciences
• Subjects: Biological Sciences
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.19.10626

Activation of Gα i -coupled receptors often causes enhancement of the inositol phosphate signal triggered by Gα q -coupled receptors. To investigate the mechanism of this synergistic receptor crosstalk, we studied the Gα i -coupled adenosine A 1 and α 2C adrenergic receptors and the Gα q -coupled bradykinin B 2 and a UTP-preferring P2Y receptor. Stimulation of either Gα i -coupled receptor expressed in COS cells increased the potency and the efficacy of inositol phosphate production by bradykinin or UTP. Likewise, overexpression of Gβ 1 γ 2 resulted in a similar increase in potency and efficacy of bradykinin or UTP. In contrast, these stimuli did not affect the potency of direct activators of Gα q ; a truncated Gβ 3 mutant had no effect on the receptor-generated signals whereas signals generated at the G-protein level were still enhanced. This suggests that the Gβγ-mediated signal enhancement occurs at the receptor level. Almost all possible combinations of Gβ 1–3 with Gγ 2–7 were equally effective in enhancing the signals of the B 2 and a UTP-preferring P2Y receptor, indicating a very broad specificity of this synergism. The enhancement of the bradykinin signal by ( i ) Gα i -activating receptor ligands or ( ii ) cotransfection of Gβγ was suppressed when the B 2 receptor was replaced by a B 2 Gβ 2 fusion protein. Gβγ enhanced the B 2 receptor-stimulated activation of G-proteins as determined by GTPγS-induced decrease in high affinity agonist binding and by B 2 receptor-enhanced [ 35 S]GTPγS binding. These findings support the concept that Gβγ exchange between Gα i - and Gα q -coupled receptors mediates this type of receptor crosstalk.