Allosteric Modulation of Functional Response of Muscarinic Receptors

Allosteric ligands modulate the binding and function of muscarinic receptors in a different way than orthosteric ligands. Unlike orthosteric ligands, their effects reach a ceiling given by cooperativity factors. This provides them with unique properties, including cooperativity-based selectivity, functional selectivity, and the ability to restore physiological-like space and time patterns of signaling under pathological conditions. Therefore, allosteric modulators of muscarinic receptors are intensively studied as possible therapeutics for pathological conditions including Alzheimer’s disease and schizophrenia. Research of allosteric modulation of muscarinic receptors has pioneered the way for a whole class A of G-protein coupled receptors and has had an impact beyond its field. In this chapter, we review the proper design of functional experiments and data analysis. We demonstrate the immense complexity of allosteric modulation of functional responses. Such complexity is reflected in the inability to determine individual microscopic constants in allosterically modulated systems. Therefore, the effects of a given allosteric modulator can be approximated by various operational models. We also discuss distinct properties of allosteric interactions that are specific to muscarinic receptors.