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J Biol Chem. 1993 Jul 5;268(19):13900-5.

Type II adenylylcyclase integrates coincident signals from Gs, Gi, and Gq.

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Department of Pharmacology, University of California School of Medicine, San Francisco 94143.


Agonists for Gi-coupled receptors augment Gs-stimulated cAMP synthesis in human embryonic kidney (HEK) 293 cells transiently expressing the type II isozyme of adenylylcyclase (AC-II). This augmentation, mediated by beta gamma subunits released from activated Gi, can be blocked by expression of the alpha subunit (alpha t) of retinal transducin (Gt), which presumably sequesters free beta gamma (Federman, A. D., Conklin, B. R., Schrader, K. A., Reed, R. R., and Bourne, H. R. (1992) Nature 356, 159-161). The alpha subunit of Gq, representing a G protein family distinct from both Gs and Gi, mimicked the inhibitory effect of alpha t, suggesting that hormonal stimulation of endogenous Gq might also release beta gamma subunits and thereby augment AC-II activity. Agonists for either of two Gq-coupled receptors did augment Gs-stimulated cAMP synthesis in HEK-293 cells expressing AC-II, but this effect was not blocked by expression of alpha t. The increased stimulation of AC-II was probably not mediated by the release of beta gamma subunits from Gq but rather by activation of protein kinase C (PKC) because of the following. (a) Phorbol esters, which activate PKC directly, elevated cAMP 2-fold in HEK-293 cells transfected with AC-II; this increase was synergistic with Gs-mediated activation of AC-II. (b) Treatments that partially inhibit or down-regulate PKC also partially prevented stimulation of AC-II by phorbol esters or by agonists for Gq-coupled receptors. Taken together, these results indicate that AC-II can integrate regulatory signals transmitted by at least three classes of G proteins; extracellular signals acting through Gs are enhanced synergistically by simultaneous signals transduced by Gi or Gq and mediated via beta gamma or PKC, respectively.

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