Hormonal stimulation of adenylyl cyclase through Gi-protein βγ subunits

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Abstract

AGONIST-BOUND receptors activate heterotrimeric (αβγ) G proteins by catalysing replacement by GTP of GDP bound to the a subunit, resulting in dissociation of α-GTP from the βγ subunits. In most cases, α-GTP carries the signal to effectors, as in hormonal stimulation1–4 and inhibition5,6of adenylyl cyclase by αs and αi, respectively. By contrast, genetic evidence in yeast7 and studies in mammalian cells8–10 suggest that βγ subunits of G proteins may also regulate effector pathways. Indeed, of the four recombinant mammalian adenylyl cyclases available for study11–14, two, adenylyl cyclases II and IV, are stimulated by βγ. This effect of βγ requires costimulation by αs-GTP14,15. This conditional pattern of effector responsiveness led to the prediction15 that receptors coupled to many G proteins will mediate elevation of cellular cyclic AMP, provided that Gs is also active. We now confirm this prediction. Coexpression of mutationally active αs with adenylyl cyclase II converted agonists that act through 'inhibitory' receptors (coupled to Gi) into stimulators of cAMP synthesis. Experiments using pertussis toxin and a putative scavenger ofβγ , the α subunit of transducin, suggest that βγ subunits of the Gi proteins mediated this stimulation. These findings assign a new signalling function to βγ subunits of Gi proteins, the conditional stimulation of cAMP synthesis by adenylyl cyclase II.

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