The dopamine D2 receptor activates inhibitory G proteins that inhibit adenylyl cyclase activity, culminating in reduced production of cAMP. Ca2+ pathways can regulate effectors that are controlled by D2 receptors; however, the molecular interactions between these two paths are unclear. Bofill-Cardona et al. provide evidence that calmodulin (CaM) directly attenuates D2 receptor activation of the inhibitory G protein Gαi1. In the presence of calcimycin, a Ca2+ ionophore, the inhibitory effect of D2 receptor agonists on production of cAMP was reduced. CaM reduced guanosine 5'-O-(3'-thiotriphosphate) (GTP-γ-S) loading in membranes containing D2 receptors and G proteins; however, this effect was not direct, because coincubation of CaM with Gαi1 and GTP-γ-S did not alter the rate of GTP-γ-S loading, and CaM did not directly bind Gαi1. The authors identified a cytoplasmic sequence in the D2 receptor, termed D2N, that bound CaM and Gαi1 simultaneously. D2N was required for the activation of Gαi1, but the presence of CaM inhibited G protein activation. Thus, these results suggest that CaM blocks the nucleotide exchange reaction on Gαi1 not by uncoupling D2 from Gαi1, but by preventing D2N-mediated enabling of the G protein activation switch.
Bofill-Cardona, E., Kudlacek, O., Yang, Q., Ahorn, H., Freissmuth, M., and Nanoff, C. (2000) Binding of calmodulin to the D2-dopamine receptor reduces receptor signaling by arresting the G protein activation switch. J. Biol. Chem. 275: 32672-32680. [Abstract] [Full Text]