Inhibition of adenylyl cyclase isoforms V and VI by various G_βγsubunits

Abstract

An intriguing development in the G-protein signaling field has been the finding that not only the Galpha subunit, but also Gbetagamma subunits, affect a number of downstream target molecules. One of the downstream targets of Gbetagamma is adenylyl cyclase, and it has been demonstrated that a number of isoforms of adenylyl cyclase can be either inhibited or stimulated by Gbetagamma subunits. Until now, adenylyl cyclase type I has been the only isoform reported to be inhibited by free Gbetagamma. Here we show by transient cotransfection into COS-7 cells of either adenylyl cyclase V or VI, together with Ggamma2 and various Gbeta subunits, that these two adenylyl cyclase isozymes are markedly inhibited by Gbetagamma. In addition, we show that Gbeta1 and Gbeta5 subunits differ in their activity. Gbeta1 transfected alone markedly inhibited adenylyl cylcase V and VI (probably by recruiting endogenous Ggamma subunits). On the other hand, Gbeta5 produced less inhibition of these isozymes, and its activity was enhanced by the addition of Ggamma2. These results demonstrate that adenylyl cyclase types V and VI are inhibited by Gbetagamma dimers and that Gbeta1 and Gbeta5 subunits differ in their capacity to regulate these adenylyl cyclase isozymes.

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…The stimulatory effects of Gbg typically require the presence of another activator such as Ga s or FSK . When overexpressed, Gbg subunits have been reported to inhibit ACs 5 and 6 (Bayewitch et al, 1998). However, cellular and in vitro assays using purified proteins display a conditional stimulation of AC5 and AC6 by Gbg Thomas and Hoffman, 1996) that involves different structural determinants in AC5 compared with AC6 (Brand et al, 2015).…”

Molecular Mechanisms for Heterologous Sensitization of Adenylate Cyclase

“…The complexity of the ␤␥ subunit regulatory effects is also evident from studies examining the effects of ␤␥ subunits on the activity of AC5 and AC6. Sequestering ␤␥ subunits enhances Heterologous Sensitization of Adenylate Cyclase drug-stimulated activity of AC5 but prevents the development of agonist-induced sensitization of both AC5 and AC6 (Avidor-Reiss et al, 1996;Thomas and Hoffman, 1996;Bayewitch et al, 1998;Rhee et al, 2000;Rubenzik et al, 2001). These observations suggest that the effects of ␤␥ subunits on the expression of heterologous sensitization are complex and may be isoform-dependent.…”

Inhibition of Adenylyl and Guanylyl Cyclase Isoforms by the Antiviral Drug Foscarnet

“…The reason for this discrepancy is not clear. Suppression of cAMP accumulation was observed, if cells were co-transfected with plasmids encoding adenylyl cyclase type V and G␤␥ (38). However, previous reconstitution experiments also did not detect an inhibitory action of ␤␥-dimers on adenylyl cyclase type V (and VI) (29).…”