scholarly journals Structural Models of Ligand-Gated Ion Channels: Sites of Action for Anesthetics and Ethanol

2013 ◽  
Vol 38 (3) ◽  
pp. 595-603 ◽  
Author(s):  
Richard W. Olsen ◽  
Guo-Dong Li ◽  
Martin Wallner ◽  
James R. Trudell ◽  
Edward J. Bertaccini ◽  
...  
Keyword(s):  
Ion Channels ◽  
Structural Models ◽  
Sites Of Action ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

scholarly journals Chasing the open-state structure of pentameric ligand-gated ion channels

2017 ◽  
Vol 149 (12) ◽  
pp. 1119-1138 ◽  
Author(s):  
Giovanni Gonzalez-Gutierrez ◽  
Yuhang Wang ◽  
Gisela D. Cymes ◽  
Emad Tajkhorshid ◽  
Claudio Grosman
Keyword(s):  
Ion Channels ◽  
Open Channel ◽  
Glycine Receptor ◽  
Structural Models ◽  
Channel Structure ◽  
Ion Permeation ◽  
Charge Selectivity ◽  
State Models ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

Remarkable advances have been made toward the structural characterization of ion channels in the last two decades. However, the unambiguous assignment of well-defined functional states to the obtained structural models has proved challenging. In the case of the superfamily of nicotinic-receptor channels (also referred to as pentameric ligand-gated ion channels [pLGICs]), for example, two different types of model of the open-channel conformation have been proposed on the basis of structures solved to resolutions better than 4.0 Å. At the level of the transmembrane pore, the open-state models of the proton-gated pLGIC from Gloeobacter violaceus (GLIC) and the invertebrate glutamate-gated Cl– channel (GluCl) are very similar to each other, but that of the glycine receptor (GlyR) is considerably wider. Indeed, the mean distances between the axis of ion permeation and the Cα atoms at the narrowest constriction of the pore (position −2′) differ by ∼2 Å in these two classes of model, a large difference when it comes to understanding the physicochemical bases of ion conduction and charge selectivity. Here, we take advantage of the extreme open-channel stabilizing effect of mutations at pore-facing position 9′. We find that the I9′A mutation slows down entry into desensitization of GLIC to the extent that macroscopic currents decay only slightly by the end of pH 4.5 solution applications to the extracellular side for several minutes. We crystallize (at pH 4.5) two variants of GLIC carrying this mutation and solve their structures to resolutions of 3.12 Å and 3.36 Å. Furthermore, we perform all-atom molecular dynamics simulations of ion permeation and picrotoxinin block, using the different open-channel structural models. On the basis of these results, we favor the notion that the open-channel structure of pLGICs from animals is much closer to that of the narrow models (of GLIC and GluCl) than it is to that of the GlyR.

Physiology and biophysics of plant ligand-gated ion channels

Plant Biology ◽  
2010 ◽  
Vol 12 ◽  
pp. 80-93 ◽  
Author(s):  
P. Dietrich ◽  
U. Anschütz ◽  
A. Kugler ◽  
D. Becker
Keyword(s):  
Ion Channels ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

scholarly journals Molecular Simulations of Hydrophobic Gating of Pentameric Ligand Gated Ion Channels: Insights into Water and Ions

2021 ◽  
Vol 125 (4) ◽  
pp. 981-994
Author(s):  
Shanlin Rao ◽  
Gianni Klesse ◽  
Charlotte I. Lynch ◽  
Stephen J. Tucker ◽  
Mark S. P. Sansom
Keyword(s):  
Ion Channels ◽  
Molecular Simulations ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

Ligand-gated ion channels as targets of neuroactive insecticides

2021 ◽  
Author(s):  
Makoto Ihara
Keyword(s):  
Ion Channels ◽  
Molecular Mechanisms ◽  
Functional Expression ◽  
X Ray ◽  
Acetylcholine Binding Protein ◽  
Site Selectivity ◽  
Future Drug ◽  
Cl Channels ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

Abstract The Cys-loop superfamily of ligand-gated ion channels (Cys-loop receptors) is one of the most ubiquitous ion channel families in vertebrates and invertebrates. Despite their ubiquity, they are targeted by several classes of pesticides, including neonicotinoids, phenylpyrazols, and macrolides such as ivermectins. The current commercialized compounds have high target site selectivity, which contributes to the safety of insecticide use. Structural analyses have accelerated progress in this field; notably, the X-ray crystal structures of acetylcholine binding protein and glutamate-gated Cl channels revealed the details of the molecular interactions between insecticides and their targets. Recently, the functional expression of the insect nicotinic acetylcholine receptor (nAChR) has been described, and detailed evaluations using the insect nAChR have emerged. This review discusses the basic concepts and the current insights into the molecular mechanisms of neuroactive insecticides targeting the ligand-gated ion channels, particularly Cys-loop receptors, and presents insights into target-based selectivity, resistance, and future drug design.

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