Structure and activation of muscarinic acetylcholine receptors

Abstract

A homology model of the M 1 muscarinic acetylcholine receptor, based on the X-ray structure of bovine rhodopsin, has been used to interpret the results of scanning and point mutagenesis studies on the receptor's transmembrane (TM) domain. Potential intramolecular interactions that are important for the stability of the protein fold have been identified. The residues contributing to the binding site for the antagonist, N-methyl scopolamine, and the agonist, acetylcholine, have been mapped. The positively charged headgroups of these ligands probably bind in a charge-stabilized aromatic cage formed by amino acid side chains in TM helices TM3, TM6 and TM7, while residues in TM4 may participate as part of a peripheral docking site. Closure of the cage around the headgroup of acetylcholine may be part of the mechanism for transducing binding energy into receptor activation, probably by disrupting a set of Van der Waals interactions between residues lying beneath the binding site that help to constrain the receptor to the inactive state, in the absence of agonist. This may trigger the reorganization of a hydrogen-bonding network between highly conserved residues in the core of the receptor, whose integrity is crucial for achievement of the activated state.

Identification of multiple allosteric sites on the M1 muscarinic acetylcholine receptor

“…This deletion did not modify ligand binding activity and shows good signaling activity [10][11][12]. The accuracy of the structure and the protonation states were analyzed with the program WHAT IF [13].…”

Epigenetic modulation of the muscarinic type 3 receptor in salivary epithelial cells

“…There are five subtypes of muscarinic receptors, M1-M5, which encode muscarinic receptor proteins that exhibit a rhodopsin-like architecture with seven transmembrane domains. 14,15 Changes in the expression and/or function of muscarinic receptors have been shown to be involved in many pathophysiological processes such as degenerative nervous diseases, chronic inflammation, and cancer. [16][17][18] In addition, muscarinic receptor activation has been shown to be involved in proliferation, angiogenesis, and tumor growth.…”

Structural Determinants of Allosteric Agonism and Modulation at the M4 Muscarinic Acetylcholine Receptor

“…The GPCR 3 superfamily comprises nearly 1000 7-transmembrane (TM)-spanning proteins that represent the largest target class for all current drugs (1). The mAChRs are prototypical family A GPCRs that mediate, along with the ionotropic nicotinic receptors, the actions of the neurotransmitter, ACh.…”