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

The heterotrimeric G-protein G(s) couples cell-surface receptors to the act ivation 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 alpha -subunits alpha (i) and alpha (q), lack such activity for al pha (s) (refs 3-6). But several RGS proteins inhibit cAMP production by G(s )-linked receptors(7,8). Here we report that RGS2 reduces cAMP production b y odorant-stimulated olfactory epithelium membranes, in which the alpha (s) family member alpha (olf) links odorant receptors to adenylyl cyclase acti vation(9,10). Unexpectedly, RGS2 reduces odorant-elicited cAMP production, not by acting on alpha (olf) but by inhibiting the activity of adenylyl cyc lase type III, the predominant adenylyl cyclase isoform in olfactory neuron s. Furthermore, whole-cell voltage clamp recordings of odorant-stimulated o lfactory neurons indicate that endogenous RGS2 negatively regulates odorant -evoked intracellular signalling. These results reveal a mechanism for cont rolling the activities of adenylyl cyclases, which probably contributes to the ability of olfactory neurons to discriminate odours.