Molecular Interactions between Ligands and Nicotinic Acetylcholine Receptors Revealed by Studies with Acetylcholine Binding Proteins

Hugo R Arias

doi:10.4172/2157-7544.1000116

Abstract

Nicotinic acetylcholine receptors (AChRs) are the best characterized ion channels representing the Cys-loop ligand-gated ion channel superfamily. Studies using Torpedo AChRs in the closed and open states andacetylcholine binding proteins (AChBPs) from different origins have elucidated the most important structural and functional features of the agonist/competitive antagonistbinding sites. The first step in recognizing the neurotransmitter ACh and other agonists is fundamental in the process of agonist-induced activation, including the opening of the intrinsic cation channel. The AChBP studies demonstrated that Loop C is an important structural feature that is modified by ligand binding. These studies defined important pharmacologic features of AChR ligands, including the differences between full and partial agonists, agonists and competitive antagonists, peptidic and non-peptidic ligands, and between high affinity and high selectivity. The studies showing the structural mechanisms by which specific ligands can activate, inhibit, and potentiate different AChR subtypes could be of therapeutic importance.

Highlights

A vast amount of evidence indicates that nicotinic acetylcholine receptors (AChRs) are important for the homeostasis and function of our body
The interaction of α-lobeline with the acetylcholine binding proteins (AChBPs) site opens a subpocket to accommodate the α-hydroxyphenetyl moiety, inducing the g-to-t conformational state [39], where the g state is the closed lobeline pocket, whereas in the endo configuration the ligand is unable to induce the opening of the lobeline pocket. These results suggest that the different occupation and orientation between full and partial agonists may produce distinct conformations of Loop C
Structural and functional studies permitted to highlight the importance of the extracellular domain for the binding of agonists, competitive antagonists, and allosteric modulators

Summary

Introduction

A vast amount of evidence indicates that nicotinic acetylcholine receptors (AChRs) are important for the homeostasis and function of our body. Three main breakthroughs in the last 10 years have helped in elucidating the functionally relevant structural features of AChRs and their cousins [1,17,18]: (1) the Torpedo AChR structures in the closed [19] and open [20] states, showing the main features at the extracellular, transmembrane, and intracellular domains (Figure 1), (2) the crystal structures of several acetylcholine binding proteins (AChBPs) showing details of the binding sites for agonists and competitive antagonists [21], and (3) the recently elucidated prokaryotic cation channels showing subtle differences between the open and closed conformations, as well as between activated (i.e., with several primary amines [22]), blocked (i.e., with several cations and open-channel blockers [23]), and inhibited (i.e., with several allosteric modulators [24]) states. AChRs are pentameric proteins with an extracellular domain that carries the binding sites for agonists (e.g., the neurotransmitter ACh and nicotine) and competitive antagonists [e.g., methyllycaconitine (MLA)].

Results

Conclusion