Inhibition of adenylyl cyclase isoforms V and VI by various Gβγ subunits

An intriguing development in the G-protein signaling field has been the finding that not only the G(alpha) subunit, but also G(beta gamma) subunits, affect a number of downstream target molecules. One of the downstream targets of G(beta gamma) is adenylyl cyclase, and it has been demonstrated that a number of isoforms of adenylyl cyclase can be either inhibited or stimulated by G(beta gamma) subunits. Until now, adenylyl cyclase type I has been the only isoform reported to be inhibited by free G(beta gamma). Here we show by transient cotransfection into COS-7 cells of either adenylyl cyclase V or VI, together with G gamma(gamma 2) and various G(beta) subunits, that these two adenylyl cyclase isozymes are markedly inhibited by G(beta gamma). In addition, we show that G(beta 1) and G(beta 5) subunits differ in their activity. G(beta 1) transfected alone markedly inhibited adenylyl cylcase V and VI (probably by recruiting endogenous G(gamma) subunits). On the other hand, G(beta 5) produced less inhibition of these isozymes, and its activity was enhanced by the addition of G(gamma 2). These results demonstrate that adenylyl cyclase types V and VI are inhibited by G(beta gamma) dimers and that G(beta 1) and G(beta 5) Subunits differ in their capacity to regulate these adenylyl cyclase isozymes.