Chapter 12 Allosteric regulation of muscarinic receptors

Abstract

This chapter describes some of the work on the location of the allosteric site on muscarinic receptors and presents recent data on the binding of strychnine to this site. Much of the work on allosteric interactions at muscarinic receptors, including the initial studies, has utilized the neuromuscular blocker gallamine. This is a highly charged ligand, bearing three positive charges, and exhibits negatively cooperative interactions with a range of muscarinic agonists and antagonists. Paradoxically, gallamine dramatically slows down the association and dissociation kinetics of quaternized muscarinic antagonists, such as N-methyl scopolamine (NMS), when it binds to muscarinic receptors—in most instances decreases in affinity are associated with faster, and not slower, kinetics. The chapter concludes that strychnine, in addition to its actions on glycine receptors, acts as an allosteric ligand at ml-m4 muscarinic receptors and is able to quantitate its binding properties. Even smaller effect of strychnine on the binding properties of NMS and acetylcholine (ACh) at ml receptors is illustrated in the chapter.