Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Neuropharmacology
2017 Oct 01;125:343-352. doi: 10.1016/j.neuropharm.2017.08.007.
Show Gene links
Show Anatomy links
A chimeric prokaryotic-eukaryotic pentameric ligand gated ion channel reveals interactions between the extracellular and transmembrane domains shape neurosteroid modulation.
Ghosh B
,
Tsao TW
,
Czajkowski C
.
???displayArticle.abstract???
Pentameric ligand-gated ion channels (pLGICs) are the targets of several clinical and endogenous allosteric modulators including anesthetics and neurosteroids. Molecular mechanisms underlying allosteric drug modulation are poorly understood. Here, we constructed a chimeric pLGIC by fusing the extracellular domain (ECD) of the proton-activated, cation-selective bacterial channel GLIC to the transmembrane domain (TMD) of the human ρ1 chloride-selective GABAAR, and tested the hypothesis that drug actions are regulated locally in the domain that houses its binding site. The chimeric channels were proton-gated and chloride-selective demonstrating the GLIC ECD was functionally coupled to the GABAρ TMD. Channels were blocked by picrotoxin and inhibited by pentobarbital, etomidate and propofol. The point mutation, ρ TMD W328M, conferred positive modulation and direct gating by pentobarbital. The data suggest that the structural machinery mediating general anesthetic modulation resides in the TMD. Proton-activation and neurosteroid modulation of the GLIC-ρ chimeric channels, however, did not simply mimic their respective actions on GLIC and GABAρ revealing that across domain interactions between the ECD and TMD play important roles in determining their actions. Proton-induced current responses were biphasic suggesting that the chimeric channels contain an additional proton sensor. Neurosteroid modulation of the GLIC-ρ chimeric channels by the stereoisomers, 5α-THDOC and 5β-THDOC, were swapped compared to their actions on GABAρ indicating that positive versus negative neurosteroid modulation is not encoded solely in the TMD nor by neurosteroid isomer structure but is dependent on specific interdomain connections between the ECD and TMD. Our data reveal a new mechanism for shaping neurosteroid modulation.
Akk,
Mutations of the GABA-A receptor alpha1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids.
2008, Pubmed
Akk,
Mutations of the GABA-A receptor alpha1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids.
2008,
Pubmed
Alqazzaz,
The Proton Responsiveness in the Extracellular Domain of GLIC Differs in the Presence of the ELIC Transmembrane Domain.
2017,
Pubmed
,
Xenbase
Alqazzaz,
Cys-loop receptor channel blockers also block GLIC.
2011,
Pubmed
Althoff,
X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors.
2014,
Pubmed
Amin,
A single hydrophobic residue confers barbiturate sensitivity to gamma-aminobutyric acid type C receptor.
1999,
Pubmed
Baenziger,
3D structure and allosteric modulation of the transmembrane domain of pentameric ligand-gated ion channels.
2011,
Pubmed
Bali,
Gating-induced conformational rearrangement of the γ-aminobutyric acid type A receptor β-α subunit interface in the membrane-spanning domain.
2012,
Pubmed
,
Xenbase
Bartos,
Structural basis of activation of cys-loop receptors: the extracellular-transmembrane interface as a coupling region.
2009,
Pubmed
Belelli,
A single amino acid confers barbiturate sensitivity upon the GABA rho 1 receptor.
1999,
Pubmed
,
Xenbase
Bertozzi,
Signal Transduction at the Domain Interface of Prokaryotic Pentameric Ligand-Gated Ion Channels.
2016,
Pubmed
,
Xenbase
Bocquet,
A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family.
2007,
Pubmed
,
Xenbase
Bocquet,
X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation.
2009,
Pubmed
Boileau,
Molecular dissection of benzodiazepine binding and allosteric coupling using chimeric gamma-aminobutyric acidA receptor subunits.
1998,
Pubmed
,
Xenbase
Bouzat,
Coupling of agonist binding to channel gating in an ACh-binding protein linked to an ion channel.
2004,
Pubmed
Bouzat,
The interface between extracellular and transmembrane domains of homomeric Cys-loop receptors governs open-channel lifetime and rate of desensitization.
2008,
Pubmed
Bracamontes,
A neurosteroid potentiation site can be moved among GABAA receptor subunits.
2012,
Pubmed
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Cecchini,
The nicotinic acetylcholine receptor and its prokaryotic homologues: Structure, conformational transitions & allosteric modulation.
2015,
Pubmed
Chen,
Anesthetic binding in a pentameric ligand-gated ion channel: GLIC.
2010,
Pubmed
Cooper,
Up-regulation of cell-surface alpha4beta2 neuronal nicotinic receptors by lower temperature and expression of chimeric subunits.
1999,
Pubmed
Dellisanti,
Site-directed spin labeling reveals pentameric ligand-gated ion channel gating motions.
2013,
Pubmed
,
Xenbase
Du,
Glycine receptor mechanism elucidated by electron cryo-microscopy.
2015,
Pubmed
Duret,
Functional prokaryotic-eukaryotic chimera from the pentameric ligand-gated ion channel family.
2011,
Pubmed
,
Xenbase
Eaton,
Modulation of the human ρ1 GABAA receptor by inhibitory steroids.
2014,
Pubmed
,
Xenbase
Eiselé,
Chimaeric nicotinic-serotonergic receptor combines distinct ligand binding and channel specificities.
1993,
Pubmed
,
Xenbase
Fourati,
Barbiturates Bind in the GLIC Ion Channel Pore and Cause Inhibition by Stabilizing a Closed State.
2017,
Pubmed
,
Xenbase
Ghosh,
Propofol binding to the resting state of the gloeobacter violaceus ligand-gated ion channel (GLIC) induces structural changes in the inter- and intrasubunit transmembrane domain (TMD) cavities.
2013,
Pubmed
,
Xenbase
Grutter,
Molecular tuning of fast gating in pentameric ligand-gated ion channels.
2005,
Pubmed
Grutter,
A chimera encoding the fusion of an acetylcholine-binding protein to an ion channel is stabilized in a state close to the desensitized form of ligand-gated ion channels.
2005,
Pubmed
Gupta,
A mechanism for acetylcholine receptor gating based on structure, coupling, phi, and flip.
2017,
Pubmed
Hassaine,
X-ray structure of the mouse serotonin 5-HT3 receptor.
2014,
Pubmed
Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed
Hilf,
X-ray structure of a prokaryotic pentameric ligand-gated ion channel.
2008,
Pubmed
Hilf,
Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel.
2009,
Pubmed
Hosie,
Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites.
2006,
Pubmed
Hénault,
Functional characterization of two prokaryotic pentameric ligand-gated ion channel chimeras - role of the GLIC transmembrane domain in proton sensing.
2017,
Pubmed
,
Xenbase
Laha,
Macroscopic kinetics of pentameric ligand gated ion channels: comparisons between two prokaryotic channels and one eukaryotic channel.
2013,
Pubmed
,
Xenbase
Lee,
Principal pathway coupling agonist binding to channel gating in nicotinic receptors.
2005,
Pubmed
Li,
Neuroactive steroids and human recombinant rho1 GABAC receptors.
2007,
Pubmed
,
Xenbase
Li,
Enantiomers of neuroactive steroids support a specific interaction with the GABA-C receptor as the mechanism of steroid action.
2006,
Pubmed
,
Xenbase
Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase
Miller,
Binding, activation and modulation of Cys-loop receptors.
2010,
Pubmed
Miller,
Crystal structure of a human GABAA receptor.
2014,
Pubmed
Moraga-Cid,
Allosteric and hyperekplexic mutant phenotypes investigated on an α1 glycine receptor transmembrane structure.
2015,
Pubmed
Morris,
Differential modulation of the gamma-aminobutyric acid type C receptor by neuroactive steroids.
1999,
Pubmed
,
Xenbase
Nemecz,
Emerging Molecular Mechanisms of Signal Transduction in Pentameric Ligand-Gated Ion Channels.
2016,
Pubmed
Nury,
[X-ray structures of general anesthetics bound to their molecular targets].
2011,
Pubmed
O'Toole,
Discrete M3-M4 intracellular loop subdomains control specific aspects of γ-aminobutyric acid type A receptor function.
2011,
Pubmed
Pan,
Structure of the pentameric ligand-gated ion channel GLIC bound with anesthetic ketamine.
2012,
Pubmed
,
Xenbase
Pan,
Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine.
2012,
Pubmed
Rienzo,
Structural requirements in the transmembrane domain of GLIC revealed by incorporation of noncanonical histidine analogs.
2014,
Pubmed
,
Xenbase
Ruesch,
An allosteric coagonist model for propofol effects on α1β2γ2L γ-aminobutyric acid type A receptors.
2012,
Pubmed
,
Xenbase
Rüsch,
Gating allosterism at a single class of etomidate sites on alpha1beta2gamma2L GABA A receptors accounts for both direct activation and agonist modulation.
2004,
Pubmed
,
Xenbase
Sancar,
Allosteric modulators induce distinct movements at the GABA-binding site interface of the GABA-A receptor.
2011,
Pubmed
,
Xenbase
Sauguet,
Crystal structures of a pentameric ligand-gated ion channel provide a mechanism for activation.
2014,
Pubmed
,
Xenbase
Sauguet,
Crystallographic studies of pharmacological sites in pentameric ligand-gated ion channels.
2015,
Pubmed
Schmandt,
A chimeric prokaryotic pentameric ligand-gated channel reveals distinct pathways of activation.
2015,
Pubmed
,
Xenbase
Serafini,
Structural domains of the human GABAA receptor 3 subunit involved in the actions of pentobarbital.
2000,
Pubmed
Shimada,
gamma-Aminobutyric acid A or C receptor? gamma-Aminobutyric acid rho 1 receptor RNA induces bicuculline-, barbiturate-, and benzodiazepine-insensitive gamma-aminobutyric acid responses in Xenopus oocytes.
1992,
Pubmed
,
Xenbase
Spurny,
Multisite binding of a general anesthetic to the prokaryotic pentameric Erwinia chrysanthemi ligand-gated ion channel (ELIC).
2013,
Pubmed
,
Xenbase
Spurny,
Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines.
2012,
Pubmed
,
Xenbase
Thompson,
The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor.
2012,
Pubmed
,
Xenbase
Tillman,
ELIC-α7 Nicotinic acetylcholine receptor (α7nAChR) chimeras reveal a prominent role of the extracellular-transmembrane domain interface in allosteric modulation.
2014,
Pubmed
Velisetty,
Structural basis for allosteric coupling at the membrane-protein interface in Gloeobacter violaceus ligand-gated ion channel (GLIC).
2014,
Pubmed
Venkatachalan,
Optimized expression vector for ion channel studies in Xenopus oocytes and mammalian cells using alfalfa mosaic virus.
2007,
Pubmed
,
Xenbase
Wang,
A single amino acid in gamma-aminobutyric acid rho 1 receptors affects competitive and noncompetitive components of picrotoxin inhibition.
1995,
Pubmed
,
Xenbase
Wang,
Intramembrane proton binding site linked to activation of bacterial pentameric ion channel.
2012,
Pubmed
Weng,
Anesthetic sensitivity of the Gloeobacter violaceus proton-gated ion channel.
2010,
Pubmed
,
Xenbase
Xiu,
A unified view of the role of electrostatic interactions in modulating the gating of Cys loop receptors.
2005,
Pubmed
,
Xenbase
Zhang,
Development of GABA-mediated, chloride-dependent inhibition in CA1 pyramidal neurones of immature rat hippocampal slices.
1991,
Pubmed
Ziemba,
Correction for Inhibition Leads to an Allosteric Co-Agonist Model for Pentobarbital Modulation and Activation of α1β3γ2L GABAA Receptors.
2016,
Pubmed
,
Xenbase
