RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III

The heterotrimeric G-protein Gs couples cell-surface receptors to the activation of adenylyl cyclases and cyclic AMP production (reviewed in refs 1, 2). RGS proteins, which act as GTPase-activating proteins (GAPs) for the G-protein α-subunits αi and αq, lack such activity for αs (refs 3,4,5,6). But several RGS proteins inhibit cAMP production by Gs-linked receptors7,8. Here we report that RGS2 reduces cAMP production by odorant-stimulated olfactory epithelium membranes, in which the αs family member αolf links odorant receptors to adenylyl cyclase activation9,10. Unexpectedly, RGS2 reduces odorant-elicited cAMP production, not by acting on αolf but by inhibiting the activity of adenylyl cyclase type III, the predominant adenylyl cyclase isoform in olfactory neurons. Furthermore, whole-cell voltage clamp recordings of odorant-stimulated olfactory neurons indicate that endogenous RGS2 negatively regulates odorant-evoked intracellular signalling. These results reveal a mechanism for controlling the activities of adenylyl cyclases, which probably contributes to the ability of olfactory neurons to discriminate odours.