TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
*1.A.9.1.1









Nicotinic acetylcholine-activated cation-selective channel, pentameric α2βγδ (immature muscle) nα2βγδ (mature muscle). A  combination of symmetric and asymmetric motions opens the gate, and the asymmetric motion involves tilting of the TM2 helices (Szarecka et al. 2007). Acetylcholine receptor δ subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita (Brownlow et al., 2001; Webster et al., 2012). Residues in TMS2 and the cytoplasmic loop linking TMSs 3 and 4 influence conductance, selectivity, gating and desensitization (Peters et al., 2010). nAChR and TRPC channel proteins (1.A.4) mediate nicotine addiction in many animals from humans to worms (Feng et al., 2006). Cholesterol recognition motifs in transmembrane domains of the human nicotinic acetylcholine receptor have been identified (Baier et al., 2011). Allosteric modulators of the α4β2 subtype of neuronal nicotinic acetylcholine receptors, the dominant type in the brain, are numerous (Pandya and Yakel, 2011).  α2β2 and α4βnicotinic acetylcholine receptors are inhibited by the β-amyloid(1-42) peptide (Pandya and Yakel, 2011b).  The A272E mutation in the alpha7 subunit gives rise to spinosad insensitivity without affecting activation by acetylcholine (Puinean et al. 2012). Inhibited by general anaesthetics (Nury et al., 2011). The X-ray crystal structures of the extracellular domain of the monomeric state of human neuronal alpha9 nicotinic acetylcholine receptor (nAChR) and of its complexes with the antagonists methyllycaconitine and alpha-bungarotoxin have been determined at resolutions of 1.8 A, 1.7 A and 2.7 A, respectively (Zouridakis et al. 2014).  Structurally similar allosteric modulators of α7 nAChR exhibit five different pharmacological effects (Gill-Thind et al. 2015).  Mutations causing slow-channel myasthenia show that a valine ring in the channel is optimized for stabilizing gating (Shen et al. 2016).  Quinoline derivatives act as agonists or antagonists depending on the type and subunit (Manetti et al. 2016). Conformational changes stabilize a twisted extracellular domain to promote transmembrane helix tilting, gate dilation, and the formation of a "bubble" that collapses to initiate ion conduction (Gupta et al. 2016).

Eukaryota
Metazoa
Acetylcholine receptors of Homo sapiens α2βγδ or ε
α (P02708)
β (P11230)
γ (P07510)
δ (Q07001)
ε (Q04844)
*1.A.9.1.2









The nicotinic acetylcholine activated cation selective channel precursor, Acr-2 or Acr-3/Unc-38 (both β and α-type chains are required for activity; levamisole-gated; activity reduced by antagonists mecamylamine and d-tubocurarine) (Squire et al., 1995; Baylis et al., 1997). nAChR and TRPC channel proteins (1.A.4) mediate nicotine addiction in many animals from humans to worms (Feng et al., 2006).

Eukaryota
Metazoa
Acr-2 or Acr-3/Unc-38 of Caenorhabditis elegans
Acr-2 (β) (P48182)
Acr-3 (β) (Q93149)
Unc-38 (α) (Q23022)
*1.A.9.1.3









Nicotinic acetylcholine receptor β-1 subunit , Accβ1 (a target of insecticides (Yu et al., 2011; Tricoire-Leignel and Thany 2010)). 

Eukaryota
Metazoa
Accβ1 of Apis cerana (F6JX92)
*1.A.9.1.4









Nicotinic acetylcholine receptor β-2 subunit, Accβ2 (a target of insecticides)

Eukaryota
Metazoa
Accβ2 of Apis cerana (F6JVF4)
*1.A.9.1.5









Acetylcholine receptor subunit alpha-type acr-5
Eukaryota
Metazoa
Acr-5 of Caenorhabditis elegans
*1.A.9.1.6









The α4β2 nicotinic acetylcholine receptor. The NMR structure of the transmembrane domain and the multiple anaesthetic binding sites are known (Bondarenko et al., 2012).  Mutations cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE; Díaz-Otero et al. 2000). 
This system contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders, i.e., schizophrenia and Alzheimer's disease. It provides an extra layer of molecular complexity by existing in two different stoichiometries determined by the subunit composition. By potentiating the action of an agonist through binding to an allosteric site, positive allosteric modulators can enhance cholinergic neurotransmission (Grupe et al. 2015).

Eukaryota
Metazoa
α4β2 NAChR of Homo sapiens 
α4 (P43681)
β2 (P17787)
*1.A.9.1.7









The alpha7 (α-7) nicotinic acetylcholine receptor of 502 aas.  Acetylcholine binding induces conformational changes that result in open channel formation; opening is blocked by α-bungarotoxin.  The protein is a homopentamer.  It interacts with RIC3 for proper folding and assembly. The nAChR, but not the glycine receptor, GlyR, exhibits hydrophobic gating (Ivanov et al. 2007). Low resolution NMR structures with associated anesthetics have been reported (Bondarenko et al. 2013).  Allosteric modulators exhibit up to 5 distinct pharmacological effects (Gill-Thind et al. 2015).  Based on pore hydration and size, a high resolution structure for the channel in the open conformation has been proposed (Chiodo et al. 2015). Agonists reduce dyskinesias in both early- and later-stage Parkinson's disease (Zhang et al. 2015). Monoterpenes inhibit the alpha7 receptor in the order: carveol > thymoquinone > carvacrol > menthone > thymol > limonene > eugenole > pulegone = carvone = vanilin. Among the monoterpenes, carveol showed the highest potency (Lozon et al. 2016).

Eukaryota
Metazoa
The homomeric α7-subunit of the acetylcholine receptor of Homo sapiens
*1.A.9.1.8









Nicotinic receptor of 560 aas and 5 TMSs

Eukaryota
Metazoa
Nicotinic receptor of Drosophila melanogaster
*1.A.9.1.9









The pentameric nicotinic acetylcholine receptor, nAChR, with α (461 aas; P02710), β (493 aas; P02712), γ (506 aas; P02714) and δ (522 aas; P02718) subunits.  The transmembrane domain of the uncoupled nAChR adopts a conformation distinct from that of the resting or desensitized state (Sun et al. 2016).  Studies with this receptor have been reviewed (Unwin 2013).  Many small molecules interact with nAChRs including d-tubocurarine, snake venom protein α-bungarotoxin (α-Bgt), and α-conotoxins, neurotoxic peptides from Conus snails. Various more recently discovered compounds of different structural classes also interact with nAChRs including the low-molecular weight alkaloids, pibocin, varacin and makaluvamines C and G. 6-Bromohypaphorine from the mollusk Hermissenda crassicornis does not bind to Torpedo nAChR but behaves as an agonist on human α7 nAChR (Kudryavtsev et al. 2015). Dimethylaniline mimics the low potency and non-competitive actions of lidocaine on nAChRs, as opposed to the high potency and voltage-dependent block by lidocaine (Alberola-Die et al. 2016).

Eukaryota
Metazoa
nAChR of Tetronarce californica (Pacific electric ray) (Torpedo californica)
*1.A.9.1.10









The nicotinic acetylcholine receptor alpha 6 isoform 1 of 505 aas and 6 or 7 putative TMSs, with one N-terminal TMS, one C-terminal TMS, and 4 or 5 centrally located TMSs.  66% identical to TC# 1.A.9.1.6.  A 3 aa deletion in the transmembrane domain causes resistance to spinosad, a macrocyclic lactone insecticide (Wang et al. 2016).

Eukaryota
Metazoa
AcChR of Plutella xylostella (Diamondback moth) (Plutella maculipennis)
*1.A.9.1.11









Acetylcholine-activated cation-selective channel, alpha-type, Acr-16 of 504 aas and 6 putative TMSs.  Four negative allosteric modulators of this channel in the parasite have been identified (Zheng et al. 2016).


Eukaryota
Metazoa
Acr-16 of Ascaris suum (Pig roundworm) (Ascaris lumbricoides)
*1.A.9.1.12









Nicotinic acetylcholine receptor with three subunits, non-alpha subunit ShAR2beta of 545 aas, as well as two additional "non-alpha subunits of 714 and 736 aas, respectively, all with 6 TMSs, 1 N-terminal, 4 central, and 1 C-terminal (Bentley et al. 2007). 

Eukaryota
Metazoa
Trimeric nAcChR of Schistosoma haematobium (Blood fluke)
*1.A.9.2.1









Serotonin (5-hydroxytryptamine)-activated cation-selective receptor/channel, 5-HT3R. Residues in TMS2 and the cytoplasmic loop linking TMSs 3 and 4 influence conductance, selectivity, gating and desensitization (Peters et al., 2010; McKinnon et al., 2011). Resveratrol enhances ion currents (Lee et al., 2011). Rings of charge within the extracellular vestibule influence ion permeation (Livesey et al., 2011).  Based on the 3-d structure, serotonin binding first induces distinct conformational fluctuations at the side chain of W156 in the highly conserved ligand-binding cage, followed by tilting-twisting movements of the extracellular domain which couple to the transmembrane TM2 helices, opening the hydrophobic gate at L260 and forming a continuous transmembrane water pathway (Yuan et al. 2016). There are 5 isoforms of 5-HT3A which include 5-HT3AB, 5-HT3AC, 5-HT3AD, and 5-HT3AE, all of which have similar but distinct pharmacological profiles compared to those of 5-HT3A receptors (Price et al. 2017). Trans-3-(4-methoxyphenyl)-N-(pentan-3-yl)acrylamide (TMPPAA) is a potent agonist with behavior different from that of 5-HT (Gasiorek et al. 2016).

Eukaryota
Metazoa
Serotonin (5HT3) receptor (5HT3R) of Homo sapiens (P46098)
*1.A.9.2.2









The heteromeric serotonin 5HT3A receptor (Hanna et al., 2000)
Eukaryota
Metazoa
The 5HT3A/5HT3B receptor of Rattus norvegicus
5HT3A (Q35563)
5HT3B (Q9JJ16)
*1.A.9.2.3









The 5-hydroxytryptamine (serotonin) receptor-3D/cation-selective ion channel, 5-HT3AR, of 454 aas.  Activated by the binding of serotonin to an extracellular orthosteric site, located at the interface of two adjacent receptor subunits. A variety of compounds modulate agonist-evoked responses of 5-HT3ARs, and other Cys-loop receptors, by binding to distinct allosteric sites (Lansdell et al. 2014).  Alternative intersubunit pathways may exist for ion translocation at the interface between the extracellular and the transmembrane domains, in addition to the one along the channel main axis. An arginine triplet located in the intracellular domain may determine the characteristic low conductance properties of the channel (Di Maio et al. 2015). The 12 Å resolution in a lipid bilayer (cryo EM) reveals topological features (Kudryashev et al. 2016; ).

Eukaryota
Metazoa
5HT3AR of Homo sapiens
*1.A.9.3.1









Adult strychnine-sensitive glycine-inhibited chloride (anion selective) heteropentameric channel (GlyR; GLRA1) consisting of α1- and β-subunits (Cascio, 2004; Sivilotti, 2010). Ivermectin potentiates glycine-induced channel activation (Wang and Lynch, 2012). Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids have been identified (Yévenes and Zeilhofer, 2011). Different subunits contribute asymmetrically to channel conductances via residues in the extracellular domain (Moroni et al., 2011; Xiong et al., 2012). Dominant and recessive mutations in GLRA1 are the major causes of hyperekplexia or startle disease (Gimenez et al., 2012).  Open channel 3-d structures are known (Mowrey et al. 2013).  Desensitization is regulated by interactions between the second and third transmembrane segments which affect the ion channel lumen near its intracellular end. The GABAAR and GlyR pore blocker, picrotoxin (TC# 8.C.1), prevents desensitization (Gielen et al. 2015).  The x-ray structure of the α1 GlyR transmembrane domain has been reported (Moraga-Cid et al. 2015), and residue S296 in hGlyR-alpha1 is involved in potentiation by Delta(9)-tetrahydrocannabinol (THC) (Wells et al. 2015).  The structure has also been elucidated by cryo EM (Du et al. 2015) and by x-ray crystalography (Huang et al. 2015). The latter presented a 3.0 A X-ray structure of the human glycine receptor-alpha3 homopentamer in complex with the high affinity, high-specificity antagonist, strychnine. The structure allowed exploration of the molecular recognition of antagonists. Comparisons with previous structures revealed a mechanism for antagonist-induced inactivation of Cys-loop receptors, involving an expansion of the orthosteric binding site in the extracellular domain that is coupled to closure of the ion pore in the transmembrane domain. The GlyR beta8-beta9 loop is an essential regulator of conformational rearrangements during ion channel opening and closing (Schaefer et al. 2017).

Eukaryota
Metazoa
Glycine receptor of heteromeric α1/ β-subunit channels (GlyR) of Homo sapiens
α1 chain (GlrA1) (P23415)
α2 chain (GlrA2) (P23416)
α3 chain (GlrA3) (O75311)
β chain (GlrB) (P48167)
*1.A.9.3.2









Photoreceptor in large monopolar cells (LMCs) histamine-gated chloride channel, HclA (Ort) (forms homomers, and heteromers with HclB; homomers resemble native LMC receptors (Pantazis et al., 2008)).
Eukaryota
Metazoa
HclA of Drosophila melanogaster (A1KYB4)
*1.A.9.3.3









Photoreceptor LMC histamine-gated chloride channel HclB (HisCl1) (forms homomers as well as heteromers with HclA; homomers and heteromers are more sensitive to histamine but with smaller conductance that of HclA (Pantazis et al., 2008)).
Eukaryota
Metazoa
HclB of Drosophila melanogaster (NP_731632)
*1.A.9.3.4









Glutamate receptor of 552 aas, GluCl-2 (Lynagh et al. 2014).

Eukaryota
Metazoa
GluCl-2 of Schistosoma mansoni (Blood fluke)
*1.A.9.4.1









Glutamate-inhibited chloride (anion-selective) channel, CIα chain
Eukaryota
Metazoa
Glutamate receptor CIα chain of Drosophila melanogaster
*1.A.9.4.2









Glutamate-gated chloride channel (GluClα or Glc-1) (α-subunits when mutated confer resistance to the antiparisitic drug, avermectin (ivermectin) (Dent et al., 2000)). A naturally occurring 4-aa deletion in the ligand binding domain of Glc-1 confers resistance to Avermectin (Ghosh et al., 2012). Several 3-d structures are known (3RIF; Hibbs and Gouaux, 2011). Ivermectin (avermectin), an anthelmintic drug, inhibits neuronal activity and muscular contractility in arthropods and nematodes, activating glutamate-gated chloride channels at nanomolar concentrations (Lynagh and Lynch, 2012; Calimet et al. 2013; Degani-Katzav et al. 2017).

Eukaryota
Metazoa
GluCl of Caenorhabditis elegans
Avr-14 (Q8IFY7)
Avr-15 (Q9TW41)
Glc-1 (O17793)
*1.A.9.4.3









Glutamate-gated chloride channel, GluC1 or Glc-4 (Yamaguchi et al., 2012). Ivermectin, an anthelminthic drug, inhibits neuronal activity and muscular contractility in arthropods and nematodes, activating glutamate-gated chloride channels at nanomolar concentrations (Lynagh and Lynch, 2012; Zemkova et al. 2014). 

Eukaryota
Metazoa
GluC1 of Haemonchus contortus (P91730)
*1.A.9.4.4









Glc-4 (GluC1) glutamate receptor of 500 aas.  The x-ray structure of several states including two apo states have been solved, revealing the gating mechanism of cys-loop receptors (Althoff et al. 2014).  Ligand-induced conformational gating has been proposed (Yoluk et al. 2015).  Effects of L-glutamate, ivermectin, ethanol and anesthetics have been examined (Heusser et al. 2016).

Eukaryota
Metazoa
Glc-4/GluC1 of Caenorhabditis elegans
*1.A.9.4.5









Glutamate-gated chloride channel of 448 aas, GluCl.  A point mutation, A309V in TMS 3, renders the protein and the organism > 11,000-fold resistant to abamectin, an insecticide of this moth, which is a global pest of cruciferous vegetables (Wang et al. 2015). Both A309V and G315E mutations contribute to target-site resistance to abamectin (Wang et al. 2017).

 

Eukaryota
Metazoa
GluCl of Plutella xylostella (Diamondback moth) (Plutella maculipennis)
*1.A.9.4.6









Glutamate-gated chloride channel exon 3c variant of 447 aas and 5 TMSs. Okaramines produced by Penicillium simplicissimum AK-40 activate l-glutamate-gated chloride channels (GluCls) and thus paralyze insects. The B. mori GluCl containing the L319F mutation retained its sensitivity to l-glutamate, but responses to ivermectin were reduced and those to okaramine B were completely eliminated (Furutani et al. 2017).

Eukaryota
Metazoa
GluCl of Bombyx mori (Silk moth)
*1.A.9.5.1









γ-Aminobutyric acid (GABA)-inhibited chloride channel. The major central endocannabinoid, 2-arachidonoyl glycerol (2-AG), directly acts at GABA(A) receptors. It potentiates the receptor at low GABA concentrations (Sigel et al., 2011). Hydrophobic anions potently and uncompetitively antagonize GABA (A) receptor function (Chisari et al., 2011). Regulated by neurosteroids; activated by pregnenolone and allopregnenalone (Costa et al., 2012). Different subunits contribute asymmetrically to channel conductances via residues in the extracellular domain (Moroni et al., 2011). Potentiated by general anaesthetics (Nury et al., 2011). Direct physical coupling between the GABA-A receptor and the KCC2 chloride transporter underlies ionic plasticity in cerebellar purkinje neurons in response to brain-derived neurotrophic factor (BDNF) (Huang et al. 2013).  GABA type A receptors, the brain's major inhibitory neurotransmitter receptors, are the targets for many general anesthetics, including volatile anesthetics, etomidate, propofol, and barbiturates.  Anesthetics usually bind at intersubunit sites (Chiara et al. 2013). Etomidate and propofol are potent general anesthetics that act via GABAA receptor allosteric co-agonist sites located at transmembrane beta+/alpha- inter-subunit interfaces. In heteromeric receptors, betaN265 (M2-15') on beta2 and beta3 subunits are important determinants of sensitivity to these drugs (Stewart et al. 2014). A P302L mutation in the gamma2 (γ2) subunit (Dravet syndrome in humans) of the mouse when expressed with the α1 and β3 subunits, produced a 90% decrease in conductance due to slow activation and enhance desensitization. It shifted the channel to a low-conductance state by reshaping the hour-glass-like pore cavity during transitions between closed, open, and desensitized states (Hernandez et al. 2017).

Eukaryota
Metazoa
GABA receptor of Rattus norvegicus
α-1 subunit precursor (P62813)
β-1 subunit precursor (P15431)
γ-1 subunit precursor (P23574)
δ subunit precursor (P18506)
ε subunit precursor (Q9ES14)
π subunit precursor (O09028)
ρ-1 subunit precurosr (O09028)
GABA associated (P60517) protein
*1.A.9.5.2









γ-aminobutyric acid (GABA)-inhibited Cl- channel, type A (α-, β- γ-subunit precursors), regulated by GABA receptor accessory protein, GABARAP (Luu et al., 2006). The anti-convulsant stiripentol acts directly on the GABA(A) receptor as a positive allosteric modulator (Fisher 2009). The major central endocannabinoid, 2-arachidonoyl glycerol (2-AG), also directly acts at GABA(A) receptors to potentiate the receptor at low GABA concentrations (Sigel et al., 2011). The recpetor is also allosterically regulated by neurosteroids via TMS1 of the beta subunit (Baker et al. 2010).  General anesthetic binding site(s) have been identified (Chiara et al., 2012). Hydrophobic anions potently and uncompetitively antagonize GABA (A) receptor function (Chisari et al., 2011). Regulated by neurosteroids; activated by pregnenolone and allopregnenalone (Costa et al., 2012). Different subunits contribute asymmetrically to channel conductances via residues in the extracellular domain (Moroni et al., 2011). Potentiated by general anaesthetics (Nury et al., 2011).  Both the alpha and beta subunits are important for activation by alcohols and anaesthetics (McCracken et al. 2010). Direct physical coupling between the GABA-A receptor (of 4 TMSs) and the KCC2 chloride transporter underlies ionic plasticity in cerebellar purkinje neurons in response to brain-derived neurotrophic factor (BDNF) (Huang et al. 2013).  An anesthetic binding site has been identified (Franks 2015). Desensitization is regulated by interactions between the second and third transmembrane segments which affect the ion channel lumen near its intracellular end. The GABAAR and GlyR pore blocker, picrotoxin (TC# 8.C.1), prevents desensitization (Gielen et al. 2015).  The mechanism of action of methaqualone (2-methyl-3-O-tolyl-4(3H)-quinazolinone, Quaalude(R)), a sedative-hypnotic and recreational drug. Methaqualone is a positive allosteric modulator (PAM) at human alpha1,2,3,5beta2,3gamma2S GABAA receptors (GABAARs) expressed, whereas it displays diverse functionalities at the alpha4,6beta1,2,3delta GABAAR subtypes, ranging from inactivity (alpha4beta1delta), through negative (alpha6beta1delta) or positive allosteric modulation (alpha4beta2delta, alpha6beta2,3delta), to superagonism (alpha4beta3delta) (Hammer et al. 2015).  The thyroid hormone L-3,5,3'-triiodothyronine (T3) inhibits GABAA receptors at micromolar concentrations and has common features with neurosteroids such as allopregnanolone (ALLOP). Westergard et al. 2015 used functional experiments on alpha2beta1gamma2 GABAA receptors to detect competitive interactions between T3 and an agonist (ivermectin, IVM) with a crystallographically determined binding site at subunit interfaces in the transmembrane domain of a homologous receptor (glutamate-gated chloride channel, GluCl). T3 and ALLOP showed competitive effects, supporting the presence of a T3 and ALLOP binding site at one or more subunit interfaces. Residues in the beta3 subunit, at or near the etomidate/propofol binding site(s), form part of the valerenic acid modulator binding pocket (Luger et al. 2015). IV general anesthetics, including propofol, etomidate, alphaxalone, and barbiturates, enhance GABAA receptor activation. These anesthetics bind in transmembrane pockets between subunits of typical synaptic GABAA receptors (Forman and Miller 2016). Carisoprodol can directly gate and allosterically modulate type A GABA (GABAA) receptors (Kumar et al. 2017).

Eukaryota
Metazoa
GABA type A receptor of Homo sapiens (α-/β-/γ-subunits + GABARAP)
α-subunit precursor (NP_000798)
β-subunit precursor (O18276)
γ-subunit precursor (NP_944494)
GABARAP (O95166)
*1.A.9.5.3









Gamma-aminobutyric acid (GABA) receptor alpha 2 subunit of 499 aas. It''s structure and sites of glycosylation and phsophorylation have been identified (Zuo et al. 2013).

Eukaryota
Metazoa
Gamma-aminobutyric receptor alpha 2 subunit of Spodoptera litura (Asian cotton leafworm)
*1.A.9.5.4









The GABA receptor consisting of α1, β3, and γ2 subunits.  Heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as the histamine receptor and mediates cellular responses to histamine. Functions as a receptor for diazepines and various anesthetics, such as pentobarbital which bind to separate allosteric effector binding sites. Functions as ligand-gated chloride channel (Jayakar et al. 2015).  GABRA1 mutations are associated with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, idiopathic familial generalized epilepsy, infantile spasms and  Dravet syndrome. Thus, GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies including Ohtahara syndrome and West syndrome (Kodera et al. 2016).

Eukaryota
Metazoa
GABA Receptor subunits α1/β3/γ2 of Homo sapiens
*1.A.9.5.5









Human GABA-A (hGABA-A) rho1 receptor of 479 aas and 4 TMSs. The guanidine compound, amiloride, antagonized the heteromeric GABA-A, glycine, and nicotinic acetylcholine receptors, but it exhibits characteristics consistent with a positive allosteric modulator for the hGABA-A rho1 receptor (Snell and Gonzales 2016).  Picrotoxinin binds to both GABAA-rho1 and -rho2 in the homomeric channels, but to GABAA-rho2 with 10x higher affinity (Naffaa and Samad 2016).

Eukaryota
Metazoa
GABA-A rho1 receptor of Homo sapiens
*1.A.9.5.6









Gamma-aminobutyric acid receptor, LCCH3 of 496 aas and 4 TMSs/ GRD of 686 aas and 4 TMSs.  LCCH3 combines with the ligand-gated ion channel subunit, GRD, to form cation-selective GABA-gated ion channels.  The heteromultimeric receptor is activated by GABA (EC50=4.5 microm), muscimol (EC50=4.8 microm) and trans-4-aminocrotonic acid (EC50=104.5 microm), and partially by cis-4-aminocrotonic acid (EC50=106.3 microm). Picrotoxin effectively blocked the GABA-gated channel (IC50=0.25 microm), but bicuculline, TPMTA, dieldrin and lindane did not. The benzodiazepines flunitrazepam and diazepam did not potentiate the GABA-evoked current (Gisselmann et al. 2004). The system has been partially characterized from the small brown planthopper, Laodelphax striatellus (Fallen), a major insect pest of crop systems in East Asia (Wei et al. 2017).

Eukaryota
Metazoa
LCCH3/GRD of Drosophila melanogaster (Fruit fly)
*1.A.9.6.1









Homomeric serotonin (5-HT)-gated chloride channel, (controlling locomotion) MOD-1 (Menard et al., 2005)
Eukaryota
Metazoa
5-HT-gated chloride channel, MOD-1 in Caernorhabditis elegans
*1.A.9.6.2









The high affinity dopamine receptor chloride channel, Lgc-53 (Ringstad et al., 2009).
Eukaryota
Metazoa
Lgc-53 of Caenorhabditis elegans (Q2PJ95)
*1.A.9.6.3









The high affinity tyramine (amine-gated) chloride channel receptor, Lgc-55 (Ringstad et al., 2009).  Activated by amphetamines (Safratowich et al. 2013).

Eukaryota
Metazoa
Lgc-55 of Caenorhabditis elegans (Q9TVI7)
*1.A.9.6.4









The low-affinity serotonin receptor, Lgc-40; also gated by choline and acetylcholine (Ringstad et al., 2009).
Eukaryota
Metazoa
Lgc-40 of Caenorhabditis elegans (Q22741)
*1.A.9.7.1









γ-aminobutyric acid (GABA)-gated cation channel, EXP-1
Eukaryota
Metazoa
EXP-1 in Caenorhabditis elegans
*1.A.9.8.1









The prokaryotic H+-gated ion channel, GlvI or GLIC (Bocquet et al., 2007), solved at 2.9 Å resolution in the open pentameric state (3EHZ_E) (Bocquet et al., 2009; Corringer et al. 2010). The basis for ion selectivity has been reported (Fritsch et al., 2011). Two stage tilting of the pore lining helices results in channel opening and closing (Zhu and Hummer, 2010). The mechanical work of opening the pore is performed primarily on the M2-M3 loop. Strong interactions of this short and conserved loop with the extracellular domain are therefore crucial to couple ligand binding to channel opening. The H+-activated GLIC has an extracellular domain between TMSs M3 and M4 but lacks the intracellular domain (ICD) which is a distinct folding domain (Goyal et al., 2011). The structural basis for alcohol modulation of GLIC has been reported (Howard et al., 2011).  The structure of the M2 TMS indicates that the charge selectivity filter is in the cytoplasmic half of the channel (Parikh et al. 2011).  Below pH 5.0, GLIC desensitizes on a time scale of minutes. During activation, the extracellular hydrophobic region undergoes changes involving outward translational movement, away from the pore axis, leading to an increase in pore diameter. The lower end of M2 remains relatively immobile (Velisetty et al., 2012). During desensitization, the intervening polar residues in the middle of M2 move closer to form a solvent-occluded barrier and thereby reveal the location of a distinct desensitization gate. In comparison to the crystal structure of GLIC, the structural dynamics of the channel in a membrane environment suggest a more loosely packed conformation with water-accessible intrasubunit vestibules penetrating from the extracellular end all the way to the middle of M2 in the closed-state (Velisetty et al. 2012).  Pore opening and closing is well understood (Zhu and Hummer 2010). X-ray structures of general anaesthetics bound to GLIC reveal a common general-anaesthetic binding site, which pre-exists in the apo-structure in the upper part of the transmembrane domain of each protomer (Nury et al., 2011). Large blockers bind in the center of the membrane, but divalent transition metal ions bind to the narrow intracellular pore entry (Hilf et al., 2010).  Alcohols and anaesthetics induce structural changes and activate ligand-gated ion channels of the LIC family by binding in intersubunit cavities (Sauguet et al. 2013; Ghosh et al. 2013).  Gating at pH 4 has been visualized by x-ray crystallography (Gonzalez-Gutierrez et al. 2013)  Site-directed spin labeling and x-ray analyses have revealed gating transition motions and mechanisms that distinguish active from desensitized states (Dellisanti et al. 2013; Sauguet et al. 2013).  Gating involves major rearrangements of the interfacial loops (Velisetty et al. 2014).  A single point mutation can change the effect of an anesthetic (desfurane; chloroform) from an inhibitor to a potentiator (Brömstrup et al. 2013).  An interhelix hydrogen bond involving His234 is important for stabilization of the open state (Rienzo et al. 2014).  The outermost M4 TMS makes distinct contributions to the maturation and gating of the related GLIC and ELIC homologs, suggesting that they exhibit divergent mechanisms of channel function (Hénault et al. 2015).  The same allosteric network may underlie the actions of various anesthetics, regardless of binding site (Joseph and Mincer 2016). GLIC and ELIC (TC# 1.A.9.9.1) may represent distinct transmembrane domain archetypes (Therien and Baenziger 2017).  Arcario et al. 2017 have demonstrate an anesthetic binding site in GLIC which is accessed through a membrane-embedded tunnel. The anesthetic interacts with a previously known site, resulting in conformational changes that produce a non-conductive state of the channel (Arcario et al. 2017).  The gating mechanism has been studied (Lev et al. 2017).

Bacteria
Cyanobacteria
GlvI or GLIC of Gloeobacter violaceus (Q7NDN8)
*1.A.9.8.2









Uncharacterized ligand-gated ion channel of 343 aas and 4 TMSs.

Bacteria
Cyanobacteria
LIC family protein of Lyngbya aestuarii
*1.A.9.8.3









Ligand-gated ion channel of 312 aas (Jaiteh et al. 2016).

Archaea
Thaumarchaeota
LIC of Thaumarchaeota archaeon N4
*1.A.9.9.1









The bacterial pentameric Cys-loop ligand-gated ion channel, ELIC. A 3.3 Å resolution structure is available (Hilf and Dutzler, 2008; Corringer et al., 2010).  X-ray analyses have identified three distinct binding sites for anaesthetics, one in the channel, one at the end of a TMS, and one in a hydrophobic pocket of the extracellular domain (Spurny et al. 2013).  Motions involving desensitization have been defined (Dellisanti et al. 2013).  Simulations indicate the similarities with and differences between the Acetylcholine receptor (Cheng et al. 2009).  This family includes members with very divergent properties (Gonzalez-Gutierrez and Grosman 2015).  Cysteamine is an agonist for ELIC (Hénault and Baenziger 2016). X-ray structures and functional measurements support a pore-blocking mechanism for the inhibitory action of short-chain alcohols which bind to the TMSs (Chen et al. 2016). GLIC (TC# 1.A.9.8.1) and ELIC may represent distinct transmembrane domain archetypes (Therien and Baenziger 2017).

Bacteria
Proteobacteria
ELIC of Dickeya chrysanthemi (Pectobacterium chrysanthemi) (Erwinia chrysanthemi)
*1.A.9.10.1









Cyc-loop anion ligand-gated receptor of 453 aas and 6 TMSs, LIC1 (Mukherjee 2015).

Eukaryota
Viridiplantae
LIC1 of Chlamydomonas reinhardtii (Chlamydomonas smithii)
*1.A.9.10.2









Uncharacterized ligand-gated ion channel of 539 aas and 4 TMSs.

Eukaryota
Viridiplantae
Uncharacterized LIC of Chlorella variabilis (Green alga)
*1.A.9.11.1









Zinc-activated ligand-gated cation channel of 412 aas and 5 TMSs, ZACN; ZAC.  Zac displays potencies and efficacies in the rank orders of H+>Cu2+>Zn2+ and H+>Zn2+>Cu2+, respectively. ZAC appears to be non-selectively permeable to monovalent cations, whereas Ca2+ and Mg2+ inhibit the channel (Trattnig et al. 2016).

Eukaryota
Metazoa
Zac of Homo sapiens