A tale of ligands big and small: An update on how pentameric ligand-gated ion channels interact with agonists and proteins

Abstract

Pentameric ligand-gated ion channels (pLGICs, also known as Cys-loop receptors) are a large family of ion channels expressed in all Bilateria and in several groups of bacteria and archaea. They are activated by small-molecule neurotransmitters to mediate fast transmission at many central and peripheral nervous system synapses and are the target of several drugs and insecticides. Here we review recent advances in the field, focussing on new insights on the structure of the agonist-binding site and on newly discovered protein-protein interactions involving pLGICs.

Identification of the Initial Steps in Signal Transduction in the α4β2 Nicotinic Receptor: Insights from Equilibrium and Nonequilibrium Simulations

“…Crystallographic studies of several water-soluble acetylcholine binding proteins (AChBPs, see, e.g., Brejc et al, 2001;Celie et al, 2004;Celie et al, 2005;Li et al, 2011;Rucktooa et al, 2012;Billen et al, 2012) have also provided insights into ACh binding, although AChBPs lack an ion channel domain. Considerable progress has been made in structural studies of other family members (for a review see Pless and Sivilotti, 2018), with several full-length structures determined of both prokaryotic channels (such as GLIC [Hilf and Dutzler, 2009;Hilf et al, 2010;Pan et al, 2012a;Prevost et al, 2012;Sauguet et al, 2013;Gonzalez-Gutierrez et al, 2013;Mowrey et al, 2013;Sauguet et al, 2014;Nemecz et al, 2017;Menny et al, 2017;Fourati et al, 2018] and ELIC [Hilf and Dutzler, 2008;Zimmermann and Dutzler, 2011;Pan et al, 2012b;Gonzalez-Gutierrez et al, 2012;Spurny et al, 2012Spurny et al, , 2013Zimmermann et al, 2012;Ulens et al, 2014;Chen et al, 2015;Bertozzi et al, 2016;Nys et al, 2016]) and eukaryotic channels (such as GlyRs [Du et al, 2015;Huang et al, 2015;Huang et al, 2017], GABA A Rs [Miller and Aricescu, 2014;Zhu et al, 2018;Miller et al, 2017;Chen et al, 2018;...…”

A critical residue in the α1M2–M3 linker regulating mammalian GABAA receptor pore gating by diazepam

“…The therapeutic effects of BZDs are conferred upon binding to and modulating the activity of GABA A Rs, which are the primary inhibitory neurotransmitter-gated ion channels in the central nervous system ( Smart and Stephenson, 2019 ). GABA A Rs are part of the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGICs) including homologous glycine (Gly), nicotinic acetylcholine (nACh), serotonin type 3 (5-HT 3 ), and zinc-activated receptors as well as prokaryotic homologs ( Pless and Sivilotti, 2018 ; Nemecz et al, 2016 ; Tasneem et al, 2004 ; Connolly and Wafford, 2004 ). Each pentameric GABA A R is comprised of subtype-specific combinations of five homologous but nonidentical subunits (α 1-6 , β 1-3 , γ 1-3 , δ, ε, π, θ, ρ 1-3 ) that together form a central chloride conducting pore ( Figure 1 ; Olsen and Sieghart, 2008 ).…”

Characterization of the dynamic resting state of a pentameric ligand-gated ion channel by cryo-electron microscopy and simulations

“…Starting from resting (apo-closed) conditions, agonist binding is thought to favor subtle structural transitions to a 'flip' or other intermediate state(s) [3] , opening of the transmembrane pore, and in most cases refractory desensitization [4]- [7] . Accordingly, a detailed understanding of pentameric channel biophysics and pharmacology requires high-quality structural templates in multiple functional states [8] .…”

“…Additional structures of GLIC have been reported in lipid-modulated [25] and a so-called "locally closed" state [26] , possibly representing gating intermediates. However, only a single GLIC X-ray structure has been reported under resting conditions (pH 7), and only to relatively low resolution (4.4 Å) [27] .…”