Abstract
Activation of Galpha(i)-coupled receptors often causes enhancement
of the inositol phosphate signal triggered by Galpha(q)-coupled receptors.
To investigate the mechanism of this synergistic receptor crosstalk,
we studied the Galpha(i)-coupled adenosine A(1) and alpha(2C) adrenergic
receptors and the Galpha(q)-coupled bradykinin B(2) and a UTP-preferring
P2Y receptor. Stimulation of either Galpha(i)-coupled receptor expressed
in COS cells increased the potency and the efficacy of inositol phosphate
production by bradykinin or UTP. Likewise, overexpression of Gbeta(1)gamma(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 Galpha(q); a truncated Gbeta(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
Gbetagamma-mediated signal enhancement occurs at the receptor level.
Almost all possible combinations of Gbeta(1-3) with Ggamma(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) Galpha(i)-activating
receptor ligands or (ii) cotransfection of Gbetagamma was suppressed
when the B(2) receptor was replaced by a B(2)Gbeta(2) fusion protein.
Gbetagamma enhanced the B(2) receptor-stimulated activation of G-proteins
as determined by GTPgammaS-induced decrease in high affinity agonist
binding and by B(2) receptor-enhanced (35)SGTPgammaS binding. These
findings support the concept that Gbetagamma exchange between Galpha(i)-
and Galpha(q)-coupled receptors mediates this type of receptor crosstalk.
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