Diverse functions of muscarinic acetylcholine receptor subtypes

Muscarinic acetylcholine receptor subtypes m1, m3 and m5 couple strongly to phosphatidylinositol turnover and hence to intracellular Ca²⁺ concentration via pertussis toxin (PTX) sensitive and insensitive G proteins. The m2 and m4 muscarinic receptor subtypes strongly inhibit adenylyl cyclase production via PTX sensitive G proteins. Additionally, the cardiac M₂ receptor is closely coupled to a K⁺ current (I(K.ACh)). To characterize this functional diversity more completely, we measured the ACh-induced Ca²⁺ responses of cells transfected with the muscarinic receptor subtypes m1, m2, m3 and m4. As expected, cells transfected with m1 or m3 receptors exhibited large dose-dependent increases in Ca²⁺ in response to ACh application. Unexpectedly, cells transfected with m2 or m4 receptors also exhibited increases in Ca²⁺ in response to agonist application. The m2- or m4-coupled responses were smaller in amplitude, required higher concentrations of agonist and were much more sensitive to PTX treatment when compared to m1- or m3-coupled responses. We discuss this remarkable diversity of function in terms of the receptor subtype's coupling to G proteins.