Kd. Lustig et al., TYPE-II ADENYLYLCYCLASE INTEGRATES COINCIDENT SIGNALS FROM GS, GI, AND GQ, The Journal of biological chemistry, 268(19), 1993, pp. 13900-13905
Agonists for G(i)-coupled receptors augment G(s)-stimulated cAMP synth
esis in human embryonic kidney (HEK) 293 cells transiently expressing
the type II isozyme of adenylylcyclase (AC-II). This augmentation, med
iated by betagamma subunits released from activated G(i), can be block
ed by expression of the alpha subunit (alpha(t)) of retinal transducin
(G(t)), which presumably sequesters free betagamma (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 G(q), representing a G pro
tein family distinct from both G(s) and G(i), mimicked the inhibitory
effect of alpha(t), suggesting that hormonal stimulation of endogenous
G(q) might also release betagamma subunits and thereby augment AC-II
activity. Agonists for either of two G(q)-coupled receptors did augmen
t G(s)-stimulated cAMP synthesis in HEK-293 cells expressing AC-II, bu
t 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 G(q) 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-I
I; this increase was synergistic with G(s)-mediated activation of AC-I
I. (b) Treatments that partially inhibit or down-regulate PKC also par
tially prevented stimulation of AC-II by phorbol esters or by agonists
for G(q)-coupled receptors. Taken together, these results indicate th
at AC-II can integrate regulatory signals transmitted by at least thre
e classes of G proteins; extracellular signals acting through G(s) are
enhanced synergistically by simultaneous signals transduced by G(i) o
r G(q) and mediated via betagamma or PKC, respectively.