A bifunctional Gα i /Gα s modulatory peptide that attenuates adenylyl cyclase activity

Signaling via G-protein coupled receptors is initiated by receptor-catalyzed nucleotide exchange on Gα subunits normally bound to GDP and Gβγ. Activated Gα·GTP then regulates effectors such as adenylyl cyclase. Except for Gβγ, no known regulators bind the adenylyl cyclase-stimulatory subunit Gαs in its GDP-bound state. We recently described a peptide, KB-752, that binds and enhances the nucleotide exchange rate of the adenylyl cyclase-inhibitory subunit Gαi. Herein, we report that KB-752 binds Gαs·GDP yet slows its rate of nucleotide exchange. KB-752 inhibits GTPγS-stimulated adenylyl cyclase activity in cell membranes, reflecting its opposing effects on nucleotide exchange by Gαi and Gαs