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An intriguing development in the G-protein signaling field has been the finding that not only the Gα subunit, but also Gβγ subunits, affect a number of downstream target molecules. One of the downstream targets of Gβγ is adenylyl cyclase, and it has been demonstrated that a number of isoforms of adenylyl cyclase can be either inhibited or stimulated by Gβγ subunits. Until now, adenylyl cyclase type I has been the only isoform reported to be inhibited by free Gβγ. Here we show by transient cotransfection into COS-7 cells of either adenylyl cyclase V or VI, together with Gγ2 and various Gβ subunits, that these two adenylyl cyclase isozymes are markedly inhibited by Gβγ. In addition, we show that Gβ1 and Gβ5 subunits differ in their activity. Gβ1 transfected alone markedly inhibited adenylyl cylcase V and VI (probably by recruiting endogenous Gγ subunits). On the other hand, Gβ5 produced less inhibition of these isozymes, and its activity was enhanced by the addition of Gγ2. These results demonstrate that ad...