Gβγ activation site in adenylyl cyclase type II Adenylyl cyclase type III is inhibited by Gβγ

The G beta gamma complex of heterotrimeric G proteins is the most outstanding example for the divergent regulation of mammalian adenylyl cyclases. The heterodimeric G beta gamma complex inhibits some isoforms, e. g. ACI, and stimulates the isoforms ACII, -IV, and -VII. Although former studies identified the QEHA region located in the C-2 domain of ACII as an important interaction site for G beta gamma, the determinant of the stimulatory effect of G beta gamma has not been detected. Here, we identified the C-1b domain as the stimulatory region using full-length adenylyl cyclase. The relevant G beta gamma signal transfer motif in IIC1b was determined as MTRYLESWGAAKPFAHL (amino acids 493-509). Amino acids of this PFAHL motif were absolutely necessary for ACII to be stimulated by G beta gamma, whereas they were dispensable for G alpha(s) or forskolin stimulation. The PFAHL motif is present in all three adenylyl cyclase isoforms that are activated by G beta gamma but is absent in other adenylyl cyclase isoforms as well as other known effectors of G beta gamma. The emerging concept of two contact sites on different molecule halves for effective regulation of adenylyl cyclase is discussed.