Fig. 1.

Schematic representation of the structures of the R-q and R-s designer receptors. The Y148C and A238G point mutations (rat M3R sequence) were introduced into the third and fifth transmembrane domains of the two receptors. These two point mutations prevent the binding of ACh, the endogenous M3R ligand (11). However, both R-q and R-s can be activated by CNO, an otherwise pharmacologically inert compound, with high potency and efficacy. Functional studies showed that CNO binding to R-q and R-s leads to the selective activation of G_q/11 and G_s, respectively (see text for details). Note that the Y148C and A238G point mutations (rat M3R sequence) correspond to the Y149C and A239G point mutations in the human M3R (11).