THE ROLE OF CHARGE INTERACTIONS IN MUSCARINIC AGONIST BINDING, AND RECEPTOR-RESPONSE COUPLING

Site-directed mutagenesis has been used to evaluate the roles of the k ey aspartate and arginine residues in transmembrane domain three of th e muscarinic receptors. The results suggest that the formation of an i onic bond between the Asp carboxylate group and the onium headgroup is essential to anchor acetylcholine in its active, bound conformation i n both binary agonist-receptor and ternary agonist-receptor-G-protein complexes, but that secondary, non-productive binding modes, promoted by non-polar forces, may contribute to binary complex formation by oth er ligands. The positive charge of the arginyl side-chain is central t o the recognition, and subsequent activation of G-proteins by the agon ist-M(1) mAChR complex.