Allosteric binding sites on muscarinic receptors

Abstract

The classical (acetylcholine) binding sites of all five subtypes of muscarinic receptors are known to be subject to allosteric regulation by a variety of small molecules. The hallmarks of such medulation in binding assays are that the allosteric ligands can alter both the affinities and the rates of association and dissociation of classical ligands. By the use of suitable combinations of allosteric ligands and appropriate models, it has been demonstrated that at least some of these ligands act via a single well-defined site. On the basis of protein-modification and mutational studies, it appears that these allosteric ligands bind to a part of the receptor that is extracellular to the classical binding site. The location of the allosteric site is likely the reason that the few ligands that have been found to increase the affinity of classical antagonists also cause a dramatic slowing of the kinetics of these classical ligands; the slowing can be so profound as to appear to reverse the increases in affinity. Fortunately, the effects of allosteric ligands on the kinetics of acetylcholine itself are not so problematic. Recent studies have described allosteric ligands that are capable of enhancing the affinity of acetylcholine in binding and response assays. Ligands of this class may prove to have quite useful applications, for example in restoring function lost due to depletion of acetylcholine.