Crosstalk between Gα(i)- and Gα(q)-coupled receptors is mediated by Gβγ exchange

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.