Ehlert_1981_Fed.Proc_40_153

Under the appropriate conditions, the binding of antagonists to the muscarinic receptor is consistent with the consequences of the law of mass action. In contrast, agonist binding is complex and can be rationalized in terms of multiple agonist binding sites having different affinities for agonists and equal affinity for antagonist. Certain correlations between the affinity constants and the pharmacological activities of agonists have led to the suggestion that differences among the subclasses of receptors are due to a single receptor molecule existing under varying degrees of conformational constraint. A variety of agents have been shown to modulate the binding properties of muscarinic receptors, including guanine nucleotides, sulfhydryl reagents, and ions. Guanine nucleotides reduce the binding of agonists by converting the heterogeneous agonist receptor population into a more homogeneous one of lower overall affinity. In contrast, antagonist binding is enhanced by guanine nucleotides. Alkylation sulfhydryl groups by N-ethylmaleimide causes a selective enhancement of agonist binding by converting low affinity sites into high affinity sites. In general, monovalent and divalent physiological ions perturb muscarinic receptor binding properties in a manner that is related to ionic strength. The modulatory effects of guanine nucleotides, sulfhydryl reagents, and ions make these agents useful tools for investigating the significance of muscarinic receptor heterogeneity.