Adenylyl cyclase type II domains involved in Gβγ stimulation

Mammalian particulate adenylyl cyclases contain two transmembrane regions (M-1 and M-2) and two cytosolic domains (C-1 and C-2) forming the catalytic core. The cytosolic domains are subdivided into a highly conserved region (part a) and a region with lower similarity (part b). Hypothetical models exist that account for the mechanism by which G alpha (s) and forskolin stimulate mammalian adenylyl cyclase. In contrast, little is known about how G beta gamma dimers regulate catalysis. The so-called QEHA region located in the C-2a domain of type II adenylyl cyclase has been proposed to represent a site of interaction. Here we show (i) that the QEHA region directly interacts with G beta gamma but (ii) that it is of minor importance for the stimulation of type II adenylyl cyclase because it can be replaced by corresponding, nonidentical regions of other adenylyl cyclase isoforms without altering the stimulatory effect of G beta gamma and (iii) that the C-1b re gion is necessary for G beta gamma to exert a stimulatory effect on adenylyl cyclase type II as in a C-1b deletion mutant the G beta gamma regulation was specifically impeded whereas the G alpha (s)- and forskolin-mediated stimulation was maintained.