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.
|Number of pages
|Trends in Pharmacological Sciences
|Published - Jan 1 1989
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