Constitutive Activity of Muscarinic Acetylcholine Receptors

Abstract

We review the literature describing constitutive activity of the five muscarinic acetylcholine receptors in native and recombinant systems and discuss the effect of constitutive activity on muscarinic pharmacology in the context of modern models of receptor activation. We include a summary of mutations found to cause constitutive activity and discuss the implications of these data for the structure, function, and activation mechanism of muscarinic receptors. Finally, we discuss the possible physiological significance of constitutive activity of muscarinic receptors, incorporating information provided by targeted deletion of each of the muscarinic subtypes.

Key Words: :

• Antagonist
• G-protein
• GPCR
• Inverse agonist
• Mutagenesis
• Transmembrane

Notes

*Amino acids are denoted by using the single letter code throughout, and unless noted, the residue number relates to the M₁ receptor. Superscripts represent the residue number according to the system of Ballesteros and Weinstein (58). The digit before the dot indicates the TM domain. The two digits after the dot show the position of the residue relative to the most conserved position in the helix, which was given the number 50. For example, in M₅, R128^3.50 in the DRY motif is the most conserved residue in TM3. The adjacent aspartate is numbered D127^3.49, and the adjacent tyrosine is Y129^3.51.

^†While this manuscript was under review, Nelson, Nahorski, and Challiss (2006, J. Pharmacol. Exp. Ther., 316:279–288) published an excellent article showing that the mutation N410Y^6.58 increases the constitutive activity of M₂ and the potency of agonists. Oxotremorine activity was differentially regulated, depending on whether they measured through the G_i/o or G_s pathways. They additionally showed inverse activity of seven antagonists some of which caused receptor up-regulation.