A bifunctional Gαi/Gαs 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.

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