TCDB is operated by the Saier Lab Bioinformatics Group

1.A.9 The Neurotransmitter Receptor, Cys loop, Ligand-gated Ion Channel (LIC) Family

Members of the LIC family of ionotropic neurotransmitter receptors (also called the cys-loop ligand gated ion channel family because of the signature cysteine loop in the amino terminal domain) are found in vertebrate and invertebrate animals and prokaryotes (TC# 1.A.9.8.1; Bocquet et al., 2007Sine and Engel, 2006Thompson et al., 2010). Because of this extracellular N-terminal ligand-binding domain, they exhibit receptor specificity for (1) acetylcholine (AcCh), (2) serotonin, (3) glycine, (4) glutamate and (5) γ-aminobutyric acid (GABA)in vertebrates. All of these receptor channels are probably hetero- or homopentameric. The best characterized are the nicotinic acetylcholine receptors which are pentameric channels of α2βγδ (immature muscle) nα2βγδ (mature muscle; see 1.A.9.1.1) (Witzemann et al., 1990; Wada et al., 1998; Khiroug et al., 2002) subunit composition. All subunits are homologous and have four transmembrane α-helices, M1-M4. Zn2+-activated cation channels of vertebrates and glutamate/serotonin-activated anion channels and GABA-gated cation channels of invertebrates are also in this family (Chen et al., 2006). Ligand binding has been reported to open the channel by a cis-trans prolylisomerization event (Cymeset al., 2005Lummis et al., 2005). An intra-membrane proton binding site has been linked to activation of a bacterial LIC (Wang et al., 2011). Agonists activate alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site distinct from the AcCholine site (Gill et al., 2011).  Molecular mechanisms of alcohol modulation (Rothberg 2012), desensitization (Keramidas and Lynch 2012) and assembly (Tsetlin et al., 2011) of nicotinic and other Cys-loop receptors have been reviewed.  Acidic residues on the sides of the channel mouth and in the extracellular domain play a role in cationic selectivity (Colón-Sáez and Yakel 2013). 

The 5-HT(3) and acetylcholine receptors (cationic ion channels) and the GABA(A) and glycine receptors (anionic ion channels) generally depolarize or hyperpolarize, respectively, the neuronal membrane. Within the amino-terminal extracellular region, all members of this family exhibit a similar architecture of ligand binding domains, and a number of key residues are completely conserved (Connolly, 2008). Zhu and Hummer (2009) have concluded that the conformational transition from open and closed states involves no major rotations of the transmembrane helices, and is instead characterized by a concerted tilting of helices M2 and M3. In addition, helix M2 changes its bending state, which results in an early closure of the pore during the open-to-closed transition. N-alcohols potential H+-activated LIC currents in prokaryotes and eukaryotes (including glycine, GABA and acetylcholine receptors) (Howard et al., 2011).

The three-dimensional structures of the protein complex in both the open and closed configurations have been solved (Miyazawa and Unwin, 2003Baenziger and Corringer, 2011). The five subunits (each of 400-500 amino acyl residues in length) are arranged in a ring with their 'M2' transmembrane helical spanners lining the central channel. The five M2 segments come together in the middle of the membrane to form the channel gate, and the gate opens upon binding of acetylcholine to distant sites in the N-terminal domains of the two α-subunits. The M2 segment determines the anion versus cation selectivity (Menard et al., 2005). These general structural features are probably valid for all members of the family. The acetylcholine receptor subunit consists of two domains, the channel domain and the ligand-binding extracellular domain. The latter is homologous to a soluble protein, the acetylcholine binding protein (AChBP), the structure of which has been solved at high resolution (Brejc et al., 2001). Nicotine interacts with nicotinic acetylcholine receptors and decreases food intake through activation of POMC neruons (Mineur et al. 2011).

Pentameric ligand-gated ion channels of the Cys-loop family mediate fast chemo-electrical transduction. Bocquet et al., 2009 presented the X-ray structure at 2.9 A resolution of the bacterial Gloeobacter violaceus pentameric ligand-gated ion channel homologue (GLIC) at pH 4.6 in an apparently open conformation. This cationic channel is permanently activated by protons. The structure is arranged as a funnel-shaped transmembrane pore widely open on the outer side and lined by hydrophobic residues. On the inner side, a 5 A constriction matches with rings of hydrophilic residues that are likely to contribute to the ionic selectivity. Structural comparison with ELIC, a bacterial homologue from Erwinia chrysanthemi solved in a presumed closed conformation (TC #1.A.9.9.1), shows a wider pore where the narrow hydrophobic constriction found in ELIC is removed. Comparative analyses of GLIC and ELIC revealed, in concert, a rotation of each extracellular beta-sandwich domain as a rigid body, interface rearrangements, and a reorganization of the transmembrane domain, involving a tilt of the M2 and M3 alpha-helices away from the pore axis. These data are consistent with a model of pore opening based on both quaternary twist and tertiary deformation (Bocquet et al., 2009).

According to Miyazawa et al. (2003), the pore is shaped by the inner ring of 5 α-helices, which curve radially to create a tapering path for the ions, and an outer ring of 15 α-helices, which coil around each other and shield the inner ring from the lipids. The gate is a constricting hydrophobic girdle at the middle of the lipid bilayer, formed by weak interactions between neighboring inner helices. When acetylcholine enters the ligand-binding domain, it triggers rotations of the protein chains on opposite sides of the entrance to the pore. These rotations are communicated through the inner helices, and open the pore by breaking the girdle apart (Miyazawa et al., 2003). (Nury et al., 2010) have presented a microsecond molecular dynamics simulation of channel gating in a nicotinic receptor homologue.

Bouzat et al. (2004) have identified structural requirements for functionally coupling the AcCh binding domain to the pore-forming domain. At least three loops in the AcCh binding domain interact with the pore domain to trigger channel opening. Modeling suggests a network of interacting loops between the two domains mediate allosteric coupling (Bouzat et al., 2004). Acetylcholine receptor channel gating is a brownian conformational cascade in which nanometer-sized domains ('Phi blocks') move in staggering sequence to link an affinity change at the transmitter binding sites with a conductance change in the pore. In the alpha-subunit, the first Phi-block to move during channel opening, is comprised of residues near the transmitter binding site, and the second is comprised of residues near the base of the extracellular domain (Purohit and Auerbach, 2007).

Muscle contraction is triggered by the opening of acetylcholine receptors at the vertebrate nerve-muscle synapse. The M2 helix of this allosteric membrane protein lines the channel, and contains a 'gate' that regulates the flow of ions through the pore. Single-molecule kinetic analysis has been used to probe the transition state of the gating conformational change and estimate the relative timing of M2 motions in the α-subunit of the murine acetylcholine receptor (Purohitet al., 2007). αM2 move in three discrete steps. The core of the channel serves both as a gate that regulates ion flow and as a hub that directs the propagation of the gating isomerization through the membrane domain of the acetylcholine receptor.

GABA interacts with three kinds of receptors, classes A, B and C. Classes A and C receptors are ligand-gated Cl- channels while class B receptors activate other channels via G proteins. GABA binding to both Class A and C receptors opens the Cl- channels, leading to increased membrane conductance. These two classes of receptors differ in their antagonist specificities and therefore are distinguished pharmacologically. These receptors consist of 6 types of subunits: α, β, γ, δ, ε, and π. There are 6 αs, 3 βs and 3 γs, and 1 each of the δ, ε and π subunits. Usually the pentamer consists of 2αs, 2 βs and 1 γ, each with 4 putative TMSs, a long N-terminus and a short C-terminus, both extracellular. These receptors possess binding sites for anti-epileptic drugs, sedatives and anesthetics. Evidence suggests that the TMS1-2 hairpin loops of the 5 subunits comprise the GABA receptor pore (Filippova et al., 2004).  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.  They bind at intersubunit sites (Chiara et al. 2013).

γ-Aminobutyric acid type A (GABAA) receptors consist of subunits whose assembly forms a neurotransmitter-gated anion channel. Subunits for this receptor constitute a large family whose members are classified according to primary structure as α, β, γ, and δ, ε, π, and ρ subunits. Recombinant expression studies of different α variants in combination with a β variant and the γ2 subunit demonstrated that GABAA receptors with distinct pharmacological properties are generated. A distinctive mark of these αxβxγ2 receptors is their ability to bind modulatory compounds such as benzodiazepines (BZs), which can modulate γ-aminobutyric acid (GABA)-gated channel activity at an allosteric site. The α variants determine the affinity of GABAA receptor subtypes toward these modulatory compounds, and members of the γ-subunit class, in particular the γ2variant, are essential for the architecture of the BZ site. Furthermore, the γ subunits impart a large unitary conductance on GABAA channels (Herb et al., 1992).

The endocannabinoid system is a lipid signaling network that modulates different brain functions. Sigel et al. (2011) showed a direct molecular interaction between the two systems. The endocannabinoid 2-arachidonoyl glycerol (2-AG) potentiates GABA(A) receptors at low concentrations of GABA. Two residues of the receptor located in the transmembrane segment M4 of β(2) confer 2-AG binding. 2-AG acts in a superadditive fashion with the neurosteroid 3α, 21-dihydroxy-5α-pregnan-20-one (THDOC) and modulates δ-subunit-containing receptors, known to be located extrasynaptically and to respond to neurosteroids. 2-AG inhibits motility in CB(1)/CB(2) cannabinoid receptor double-KO, whereas β(2)-KO mice show hypermotility. The identification of a functional binding site for 2-AG in the GABA(A) receptor may have far-reaching consequences for the study of locomotion and sedation (Sigel et al., 2011).

γ2 and δ subunits share approximately 35% sequence identity with α and β subunits and form functional GABA-gated chloride channels when expressed alone in vitro. The γ2 subunit is the rat homologue of the human γ2 subunit shown to be important for benzodiazepine pharmacology (Shivers et al., 1989). Functional GABA receptors mediating Cl- uptake in a picrotoxin-sensitive process (α5, β1, γ1) have been identified and shown to be functional in renal proximal tubular cells (Sarang et al., 2008).

A novel type of GABA receptor has been characterized (Beg and Jorgensen, 2003). It is an excitatory GABA gated cation channel (TC #1.A.9.7.1). This channel is the EXP-1 receptor of the nematode, C. elegans. It is as divergent in sequence from the A and C class anion selective GABA receptors as it is from the other ligand-gated ion channel proteins in TCDB. It therefore represents a new subfamily in the LIC family. Inhibitory glycine receptors (GlyR) mediate Cl- influx and bind strychnine with nanomolar affinity. They are present in various nervous tissues (spinal cord, brain stem, caudal brain and retina (Cascio, 2004). Reduced activities of mutants often results in channelopathies involving muscle tone regulation including human startle disease (hyperekplexia). There are multiple subunit subtypes in humans (α1, α2, α3, α4 and β subunits) (Cascio, 2004)). Alternative splicing also occurs. In adults, the most common pentameric form consists of α1and β subunits. The M2α-helix region peptide of α1 GlyR in lipid vesicles forms chloride-conducting pores, and sympathetic M2-based peptides form Cl- channels in cell membranes (Mitchell et al., 2000).

There are seven classes of serotonin (5 hydroxytryptamine (5HT) receptors, six of which are G-protein linked, plus one of which is a homo- or heteropentameric ligand gated non-specific cation channel (TC #1.A.9.2.1 and 2) of the LIC family (Reeves and Lummis, 2002). Anion selective serotonin receptors may be present in C. elegans (TC #1.A.9.6.1). As for other LIC family members, four transmembrane hydrophobic segments (TMSs) (M1-M4) are predicted by hydropathy analysis.

The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] mediates rapid excitatory responses in peripheral and central neurons by activating ligand-gated ion channels (5-HT3 receptors). These receptors are expressed in a variety of peripheral ganglia, where they are thought to modulate responses to pain, and to control reflexes of the enteric and cardiovascular systems. In the central nervous system, 5-HT3 receptors have been implicated in the control of emesis, and antagonists of 5-HT3 receptors have found clinical use for suppression of the nausea that accompanies postoperative recovery and many cancer therapies. Most families of ligand-gated ion channels are composed of multiple subunit types that assemble in alternative combinations to achieve functional diversity (Hanna et al., 2000).

Recombinant expression of 5-HT3A subunits alone yields functional 5-HT3receptors, but, heteromeric assemblies of the human 5-HT3A and 5-HT3B subunits more closely resemble native 5-HT3 receptors of rodent ganglia with respect to their single-channel conductance and permeability to Ca2+ ions. Consequently, it is likely that rodent ganglia normally express heteromeric 5-HT3 receptors. However, the 5-HT3 receptors of different species display several distinctive properties, particularly with respect to their pharmacological profiles (Hanna et al., 2000).

The channel protein complexes of the LIC family preferentially transport cations or anions depending on the channel (e.g., the acetylcholine and serotonin receptors are cation-selective while glycine receptors are anion-selective). α1β heteromeric receptors are likely to be the predominant synaptic form of glycine receptors in adult mammals. (Burzomato et al., 2004). Glycine binding increases Cl-conductance producing superpolarization and inhibition of neuronal firing. Gephyrin (Q9NQX3) anchors glycine receptors to subsynaptic microtubules.

Several homologous bacterial LIC family members have been identified (eg, 1.A.9.8-9) Hilf and Dutzler (2008) have presented X-ray structures of a pentameric ligand-gated ion channel from the bacterium Erwinia chrysanthemi at 3.3 A resolution. This high resolution structure provides a model system for the investigation of the general mechanisms of ion permeation and gating within the LIC family.

Hibbs and Gouaux (2011) presented the three-dimensional structure of an inhibitory anion-selective Cys-loop receptor, the homopentameric Caenorhabditis elegans glutamate-gated chloride channel α (GluCl), at 3.3 Å resolution. The structures were determined with the allosteric agonist ivermectin (PDB#3RIF), the neurotransmitter L-glutamate and the open-channel blocker picrotoxin. Ivermectin, used to treat river blindness, binds in the transmembrane domain of the receptor and stabilizes an open-pore conformation. Glutamate binds in the classical agonist site at subunit interfaces, and picrotoxin directly occludes the pore near its cytosolic base. GluCl provides a framework for understanding mechanisms of fast inhibitory neurotransmission and allosteric modulation of Cys-loop receptors in general.

Cys loop, glutamate, and P2X receptors are ligand-gated ion channels (LGICs) with 5, 4, and 3 protomers, respectively. Agonists and competitive antagonists apparently induce opposite motions of the binding pocket (Du et al., 2012). Agonists, usually small, induce closure of the binding pocket, leading to opening of the channel pore, whereas antagonists, usually large, induce opening of the binding pocket, thereby stabilizing the closed pore.

References associated with 1.A.9 family:

Alexander, S.P.H. and J.A. Peters. (1997). Receptor and ion channel nomenclature supplement. Trends Pharmacol. Sci. 18: 4-6; 36-40; 42-44.
Althoff, T., R.E. Hibbs, S. Banerjee, and E. Gouaux. (2014). X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors. Nature 512: 333-337. 25143115
Ashcroft, F.M. (2000). Ion Channels and Disease. San Diego: Academic Press.
Baenziger, J.E. and P.J. Corringer. (2011). 3D structure and allosteric modulation of the transmembrane domain of pentameric ligand-gated ion channels. Neuropharmacology 60: 116-125. 20713066
Baier, C.J., J. Fantini, and F.J. Barrantes. (2011). Disclosure of cholesterol recognition motifs in transmembrane domains of the human nicotinic acetylcholine receptor. Sci Rep 1: 69. 22355588
Baker, C., B.L. Sturt, and B.A. Bamber. (2010). Multiple roles for the first transmembrane domain of GABAA receptor subunits in neurosteroid modulation and spontaneous channel activity. Neurosci Lett 473: 242-247. 20193738
Baylis, H.A., K. Matsuda, M.D. Squire, J.T. Fleming, R.J. Harvey, M.G. Darlison, E.A. Barnard, and D.B. Sattelle. (1997). ACR-3, a Caenorhabditis elegans nicotinic acetylcholine receptor subunit. Molecular cloning and functional expression. Receptors Channels 5: 149-58. 9606719
Beg, A.A. and E.M. Jorgensen. (2003). EXP-1 is an excitatory GABA-gated cation channel. Nature Neurosci. (in press). 14555952
Bocquet, N., H. Nury, M. Baaden, C. Le Poupon, J.P. Changeux, M. Delarue, and P.J. Corringer. (2009). X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature 457: 111-114. 18987633
Bocquet, N., L. Prado de Carvalho, J. Cartaud, J. Neyton, C. Le Poupon, A. Taly, T. Grutter, J.P. Changeux, and P.J. Corringer. (2007). A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family. Nature 445: 116-119. 17167423
Bondarenko, V., D. Mowrey, L.T. Liu, Y. Xu, and P. Tang. (2012). NMR resolved multiple anesthetic binding sites in the TM domains of the α4β2 nAChR. Biochim. Biophys. Acta. [Epub: Ahead of Print] 23000369
Bondarenko, V., D.D. Mowrey, T.S. Tillman, E. Seyoum, Y. Xu, and P. Tang. (2013). NMR structures of the human α7 nAChR transmembrane domain and associated anesthetic binding sites. Biochim. Biophys. Acta. [Epub: Ahead of Print] 24384062
Bouzat, C., F. Gumilar, G. Spitzmaul, H.-L. Wang, D. Rayes, S.B. Hansen, P. Taylor, and S.M. Sine. (2004). Coupling of agonist binding to channel gating in an ACh-binding protein linked to an ion channel. Nature 430: 896-900. 15318223
Brejc, K., W.J. van Dijk, R.V. Klaassen, M. Schuurmans, J. van der Oost, A.B. Smit, and T.K. Sixma. (2001). Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411: 269-276. 11357122
Brömstrup, T., R.J. Howard, J.R. Trudell, R.A. Harris, and E. Lindahl. (2013). Inhibition versus potentiation of ligand-gated ion channels can be altered by a single mutation that moves ligands between intra- and intersubunit sites. Structure 21: 1307-1316. 23891290
Brownlow, S., R. Webster, R. Croxen, M. Brydson, B. Neville, J.P. Lin, A. Vincent, J. Newsom-Davis, and D. Beeson. (2001). Acetylcholine receptor delta subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita. J. Clin. Invest. 108: 125-130. 11435464
Burzomato, V., M. Beato, P.J. Groot-Kormelink, D. Colquhoun, and L.G. Sivilotti. (2004). Single-channel behavior of heteromeric α1β glycine receptors: an attempt to detect a conformational change before the channel opens. J. Neurosci. 24: 10924-10940. 15574743
Cascio M. (2004). Structure and function of the glycine receptor and related nicotinicoid receptors. J. Biol. Chem. 279: 19383-19386. 15023997
Chen, Y., K. Reilly, and Y. Chang. (2006). Evolutionarily conserved allosteric network in the Cys loop family of ligand-gated ion channels revealed by statistical covariance analyses. J. Biol. Chem. 281: 18184-18192. 16595655
Chiara, D.C., S.S. Jayakar, X. Zhou, X. Zhang, P.Y. Savechenkov, K.S. Bruzik, K.W. Miller, and J.B. Cohen. (2013). Specificity of intersubunit general anesthetic-binding sites in the transmembrane domain of the human α1β3γ2 γ-aminobutyric acid type A (GABAA) receptor. J. Biol. Chem. 288: 19343-19357. 23677991
Chiara, D.C., Z. Dostalova, S.S. Jayakar, X. Zhou, K.W. Miller, and J.B. Cohen. (2012). Mapping general anesthetic binding site(s) in human α1β3 γ-aminobutyric acid type A receptors with [³H]TDBzl-etomidate, a photoreactive etomidate analogue. Biochemistry 51: 836-847. 22243422
Chisari, M., K. Wu, C.F. Zorumski, and S. Mennerick. (2011). Hydrophobic anions potently and uncompetitively antagonize GABA(A) receptor function in the absence of a conventional binding site. Br J Pharmacol 164: 667-680. 21457224
Colón-Sáez, J.O. and J.L. Yakel. (2013). A mutation in the extracellular domain of the α7 nAChR reduces calcium permeability. Pflugers Arch. [Epub: Ahead of Print] 24177919
Connolly, C.N. (2008). Trafficking of 5-HT(3) and GABA(A) receptors (Review). Mol. Membr. Biol. 25: 293-301. 18446615
Corringer, P.J., M. Baaden, N. Bocquet, M. Delarue, V. Dufresne, H. Nury, M. Prevost, and C. Van Renterghem. (2010). Atomic structure and dynamics of pentameric ligand-gated ion channels: new insight from bacterial homologues. J. Physiol. 588: 565-572. 19995852
Costa, B., E. Da Pozzo, and C. Martini. (2012). Translocator protein as a promising target for novel anxiolytics. Curr Top Med Chem 12: 270-285. 22204481
Cymes, G.D., Y. Ni, and C. Grosman. (2005). Probing ion-channel pores one proton at a time. Nature 438: 975-980. 16355215
Dellisanti, C.D., B. Ghosh, S.M. Hanson, J.M. Raspanti, V.A. Grant, G.M. Diarra, A.M. Schuh, K. Satyshur, C.S. Klug, and C. Czajkowski. (2013). Site-directed spin labeling reveals pentameric ligand-gated ion channel gating motions. PLoS Biol 11: e1001714. 24260024
Dent, J.A., M.M. Smith, D.K. Vassilatis, and L. Avery. (2000). The genetics of ivermectin resistance in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 97: 2674-2679. 10716995
Du, J., H. Dong, and H.X. Zhou. (2012). Size matters in activation/inhibition of ligand-gated ion channels. Trends Pharmacol Sci. [Epub: Ahead of Print] 22789930
Feng, Z., W. Li, A. Ward, B.J. Piggott, E.R. Larkspur, P.W. Sternberg, and X.Z. Xu. (2006). A C. elegans model of nicotine-dependent behavior: regulation by TRP-family channels. Cell 127: 621-633. 17081982
Filippova, N., V.E. Wotring, and D.S. Weiss. (2004). Evidence that the TM1-TM2 loop contributes to the ρ1 GABA receptor pore. J. Biol. Chem. 279: 20906-20914. 15007065
Fritsch, S., I. Ivanov, H. Wang, and X. Cheng. (2011). Ion selectivity mechanism in a bacterial pentameric ligand-gated ion channel. Biophys. J. 100: 390-398. 21244835
Ghosh, B., K.A. Satyshur, and C. Czajkowski. (2013). 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. J. Biol. Chem. [Epub: Ahead of Print] 23640880
Ghosh, R., E.C. Andersen, J.A. Shapiro, J.P. Gerke, and L. Kruglyak. (2012). Natural variation in a chloride channel subunit confers avermectin resistance in C. elegans. Science 335: 574-578. 22301316
Gill, J.K., M. Savolainen, G.T. Young, R. Zwart, E. Sher, and N.S. Millar. (2011). Agonist activation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site. Proc. Natl. Acad. Sci. USA 108: 5867-5872. 21436053
Gimenez, C., G. Perez-Siles, J. Martinez-Villarreal, E. Arribas-Gonzalez, E. Jimenez, E. Nunez, J. de Juan-Sanz, E. Fernandez-Sanchez, N. Garcia-Tardon, I. Ibanez, V. Romanelli, J. Nevado, V.M. James, M. Topf, S.K. Chung, R.H. Thomas, L.R. Desviat, C. Aragon, F. Zafra, M.I. Rees, P. Lapunzina, R.J. Harvey, and B. Lopez-Corcuera. (2012). A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2. J. Biol. Chem. [Epub: Ahead of Print] 22753417
Gonzalez-Gutierrez, G., L.G. Cuello, S.K. Nair, and C. Grosman. (2013). Gating of the proton-gated ion channel from Gloeobacter violaceus at pH 4 as revealed by X-ray crystallography. Proc. Natl. Acad. Sci. USA 110: 18716-18721. 24167270
Goyal, R., A.A. Salahudeen, and M. Jansen. (2011). Engineering a prokaryotic Cys-loop receptor with a third functional domain. J. Biol. Chem. 286: 34635-34642. 21844195
Hanna, M.C., P.A. Davies, T.G. Hales, and E.F. Kirkness. (2000). Evidence for expression of heteromeric serotonin 5-HT(3) receptors in rodents. J. Neurochem. 75: 240-247. 10854267
Herb, A., W. Wisden, H. Lüddens, G. Puia, S. Vicini, and P.H. Seeburg. (1992). The third γ subunit of the gamma-aminobutyric acid type A receptor family. Proc. Natl. Acad. Sci. U.S.A. 89: 1433-1437. 1311098
Hibbs, R.E. and E. Gouaux. (2011). Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature 474: 54-60. 21572436
Hilf, R.J., and R. Dutzler. (2008). X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature 452: 375-379. 18322461
Hilf, R.J., C. Bertozzi, I. Zimmermann, A. Reiter, D. Trauner, and R. Dutzler. (2010). Structural basis of open channel block in a prokaryotic pentameric ligand-gated ion channel. Nat Struct Mol Biol 17: 1330-1336. 21037567
Howard, R.J., S. Murail, K.E. Ondricek, P.J. Corringer, E. Lindahl, J.R. Trudell, and R.A. Harris. (2011). Structural basis for alcohol modulation of a pentameric ligand-gated ion channel. Proc. Natl. Acad. Sci. USA 108: 12149-12154. 21730162
Huang, Y., J.J. Wang, and W.H. Yung. (2013). Coupling Between GABA-A Receptor and Chloride Transporter Underlies Ionic Plasticity in Cerebellar Purkinje Neuron.s. Cerebellum. [Epub: Ahead of Print] 23341142
Keramidas, A. and J.W. Lynch. (2012). An outline of desensitization in pentameric ligand-gated ion channel receptors. Cell Mol Life Sci. [Epub: Ahead of Print] 22936353
Khiroug, S.S., P.C. Harkness, P.W. Lamb, S.N. Sudweeks, L. Khiroug, N.S. Millar, and J.L. Yakel. (2002). Rat nicotinic ACh receptor alpha7 and beta2 subunits co-assemble to form functional heteromeric nicotinic receptor channels. J. Physiol. 540: 425-434. 11956333
Lansdell, S.J., C. Sathyaprakash, A. Doward, and N.S. Millar. (2014). Activation of Human 5-HT3 Receptors Via an Allosteric Transmembrane Site. Mol Pharmacol. [Epub: Ahead of Print] 25338672
Lee, B.H., S.H. Hwang, S.H. Choi, T.J. Shin, J. Kang, S.M. Lee, and S.Y. Nah. (2011). Resveratrol enhances 5-hydroxytryptamine type 3A receptor-mediated ion currents: the role of arginine 222 residue in pre-transmembrane domain I. Biol Pharm Bull 34: 523-527. 21467640
Livesey, M.R., M.A. Cooper, J.J. Lambert, and J.A. Peters. (2011). Rings of charge within the extracellular vestibule influence ion permeation of the 5-HT3A receptor. J. Biol. Chem. 286: 16008-16017. 21454663
Lummis, S.C., D.L. Beene, L.W. Lee, H.A. Lester, R.W. Broadhurst, and D.A. Dougherty. (2005). Cis-trans isomerization at a proline opens the pore of a neurotransmitter-gated ion channel. Nature 438: 248-252. 16281040
Luu, T., P.W. Gage, and M.L. Tierney. (2006). GABA increases both the conductance and mean open time of recombinant GABAA channels co-expressed with GABARAP. J. Biol. Chem. 281: 35699-35708. 16954214
Lynagh, T. and J.W. Lynch. (2012). Molecular mechanisms of Cys-loop ion channel receptor modulation by ivermectin. Front Mol Neurosci 5: 60. 22586367
McCracken, M.L., C.M. Borghese, J.R. Trudell, and R.A. Harris. (2010). A transmembrane amino acid in the GABAA receptor β2 subunit critical for the actions of alcohols and anesthetics. J Pharmacol Exp Ther 335: 600-606. 20826568
McKinnon, N.K., D.C. Reeves, and M.H. Akabas. (2011). 5-HT3 receptor ion size selectivity is a property of the transmembrane channel, not the cytoplasmic vestibule portals. J Gen Physiol 138: 453-466. 21948949
Menard, C., H.R. Horvitz, and S. Cannon. (2005). Chimeric mutations in the M2 segment of the 5-hydroxytryptamine-gated chloride channel MOD-1 define a minimal determinant of anion/cation permeability. J. Biol. Chem. 280: 27502-27507. 15878844
Mineur, Y.S., A. Abizaid, Y. Rao, R. Salas, R.J. DiLeone, D. Gündisch, S. Diano, M. De Biasi, T.L. Horvath, X.B. Gao, and M.R. Picciotto. (2011). Nicotine decreases food intake through activation of POMC neurons. Science 332: 1330-1332. 21659607
Mitchell K.E., T. Iwamoto, J. Tomich, L.C. Freeman. (2000). A synthetic peptide based on a glycine-gated chloride channel induces a novel chloride conductance in isolated epithelial cells. Biochim. Biophys. Acta. 1466: 47-60. 10825430
Miyazawa, A. Y. Fujiyoshi, and N. Unwin. (2003). Structure and gating mechanism of the acetylcholine receptor pore. Nature 423: 949-955. 12827192
Moroni, M., J.O. Meyer, C. Lahmann, and L.G. Sivilotti. (2011). In glycine and GABA(A) channels, different subunits contribute asymmetrically to channel conductance via residues in the extracellular domain. J. Biol. Chem. 286: 13414-13422. 21343294
Nury, H., C. Van Renterghem, Y. Weng, A. Tran, M. Baaden, V. Dufresne, J.P. Changeux, J.M. Sonner, M. Delarue, and P.J. Corringer. (2011). X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. Nature 469: 428-431. 21248852
Nury, H., F. Poitevin, C. Van Renterghem, J.P. Changeux, P.J. Corringer, M. Delarue, and M. Baaden. (2010). One-microsecond molecular dynamics simulation of channel gating in a nicotinic receptor homologue. Proc. Natl. Acad. Sci. USA 107: 6275-6280. 20308576
Pandya, A. and J.L. Yakel. (2011). Allosteric modulator Desformylflustrabromine relieves the inhibition of α2β2 and α4β2 nicotinic acetylcholine receptors by β-amyloid(1-42) peptide. J Mol Neurosci 45: 42-47. 21424792
Pandya, A. and J.L. Yakel. (2011). Allosteric modulators of the α4β2 subtype of neuronal nicotinic acetylcholine receptors. Biochem Pharmacol 82: 952-958. 21596025
Pantazis, A., A. Segaran, C.H. Liu, A. Nikolaev, J. Rister, A.S. Thum, T. Roeder, E. Semenov, M. Juusola, and R.C. Hardie. (2008). Distinct roles for two histamine receptors (HclA and HclB) at the Drosophila photoreceptor synapse. J. Neurosci. 28: 7250-7259. 18632929
Parikh, R.B., M. Bali, and M.H. Akabas. (2011). Structure of the M2 transmembrane segment of GLIC, a prokaryotic Cys loop receptor homologue from Gloeobacter violaceus, probed by substituted cysteine accessibility. J. Biol. Chem. 286: 14098-14109. 21362624
Peters, J.A., M.A. Cooper, J.E. Carland, M.R. Livesey, T.G. Hales, and J.J. Lambert. (2010). Novel structural determinants of single channel conductance and ion selectivity in 5-hydroxytryptamine type 3 and nicotinic acetylcholine receptors. J. Physiol. 588: 587-596. 19933751
Puinean, A.M., S.J. Lansdell, T. Collins, P. Bielza, and N.S. Millar. (2012). A nicotinic acetylcholine receptor transmembrane point mutation (G275E) associated with resistance to spinosad in Frankliniella occidentalis. J Neurochem. [Epub: Ahead of Print] 23016960
Purohit, P. and A. Auerbach. (2007). Acetylcholine receptor gating: movement in the α-subunit extracellular domain. J. Gen. Physiol. 130(6):569-579. 18040059
Purohit, P., A. Mitra, and A. Auerbach. (2007). A stepwise mechanism for acetylcholine receptor channel gating. Nature 446: 930-933. 17443187
Ranganathan, R., S.C. Cannon and H.R. Horvitz. (2000). MOD-1 is a serotonin-gated chloride channel that modulates locomotory behavior in C. elegans. Nature 408: 470-473. 11100728
Reeves, D.C. and S.C.R. Lummis. (2002). The molecular basis of the structure and function of the 5-HT3 receptor: a model ligand-gated ion channel. Mol. Membrane Biol. 19: 11-26. 11989819
Ringstad, N., N. Abe, and H.R. Horvitz. (2009). Ligand-gated chloride channels are receptors for biogenic amines in C. elegans. Science 325: 96-100. 19574391
Rothberg, B.S. (2012). The BK channel: a vital link between cellular calcium and electrical signaling. Protein Cell. [Epub: Ahead of Print] 22996175
Safratowich, B.D., C. Lor, L. Bianchi, and L. Carvelli. (2013). Amphetamine activates an amine-gated chloride channel to generate behavioral effects in Caenorhabditis elegans. J. Biol. Chem. 288: 21630-21637. 23775081
Sarang, S.S., S.M. Lukyanova, D.D. Brown, B.S. Cummings, S.R. Gullans, and R.G. Schnellmann. (2008). Identification, coassembly, and activity of γ- aminobutyric acid receptor subunits in renal proximal tubular cells. J. Pharmacol. Exp. Ther. 324: 376-382. 17959749
Sauguet, L., A. Shahsavar, F. Poitevin, C. Huon, A. Menny, A. Nemecz, A. Haouz, J.P. Changeux, P.J. Corringer, and M. Delarue. (2013). Crystal structures of a pentameric ligand-gated ion channel provide a mechanism for activation. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print] 24367074
Sauguet, L., R.J. Howard, L. Malherbe, U.S. Lee, P.J. Corringer, R. Adron Harris, and M. Delarue. (2013). Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel. Nat Commun 4: 1697. 23591864
Shivers, B.D., I. Killisch, R. Sprengel, H. Sontheimer, M. Köhler, P.R. Schofield, and P.H. Seeburg. (1989). Two novel GABAA receptor subunits exist in distinct neuronal subpopulations. Neuron. 3: 327-337. 2561970
Sigel, E., R. Baur, I. Rácz, J. Marazzi, T.G. Smart, A. Zimmer, and J. Gertsch. (2011). The major central endocannabinoid directly acts at GABA(A) receptors. Proc. Natl. Acad. Sci. USA 108: 18150-18155. 22025726
Sine, S.M. and A.G. Engel. (2006). Recent advances in Cys-loop receptor structure and function. Nature 440: 448-455. 16554804
Sivilotti, L.G. (2010). What single-channel analysis tells us of the activation mechanism of ligand-gated channels: the case of the glycine receptor. J. Physiol. 588: 45-58. 19770192
Spurny, R., B. Billen, R.J. Howard, M. Brams, S. Debaveye, K.L. Price, D.A. Weston, S.V. Strelkov, J. Tytgat, S. Bertrand, D. Bertrand, S.C. Lummis, and C. Ulens. (2013). Multi-Site Binding Of A General Anesthetic To The Prokaryotic Pentameric Ligand-Gated Ion Channel ELIC. J. Biol. Chem. [Epub: Ahead of Print] 23364792
Squire, M.D., C. Tornøe, H.A. Baylis, J.T. Fleming, E.A. Barnard, and D.B. Sattelle. (1995). Molecular cloning and functional co-expression of a Caenorhabditis elegans nicotinic acetylcholine receptor subunit (acr-2). Receptors Channels 3: 107-115. 8581398
Thompson, A.J., H.A. Lester, and S.C. Lummis. (2010). The structural basis of function in Cys-loop receptors. Q. Rev. Biophys. 43: 449-499. 20849671
Tricoire-Leignel, H. and S.H. Thany. (2010). Identification of critical elements determining toxins and insecticide affinity, ligand binding domains and channel properties. Adv Exp Med Biol 683: 45-52. 20737787
Tsetlin, V., D. Kuzmin, and I. Kasheverov. (2011). Assembly of nicotinic and other Cys-loop receptors. J Neurochem 116: 734-741. 21214570
Unwin, N. (1995). Acetylcholine receptor channel imaged in the open state. Nature 373: 37-43. 7800037
Velisetty, P., S.V. Chalamalasetti, and S. Chakrapani. (2012). Conformational transitions underlying pore opening and desensitization in membrane-embedded GLIC. J. Biol. Chem. [Epub: Ahead of Print] 22977232
Velisetty, P., S.V. Chalamalasetti, and S. Chakrapani. (2014). Structural basis for allosteric coupling at the membrane-protein interface in Gloeobacter violaceus ligand-gated ion channel (GLIC). J. Biol. Chem. 289: 3013-3025. 24338475
Wang HL., Cheng X. and Sine SM. (2012). Intramembrane proton binding site linked to activation of bacterial pentameric ion channel. J Biol Chem. 287(9):6482-9. 22084238
Wang, Q. and J.W. Lynch. (2012). A comparison of glycine- and ivermectin-mediated conformational changes in the glycine receptor ligand-binding domain. Int J Biochem. Cell Biol. 44: 335-340. 22094187
Webster, R., S. Maxwell, H. Spearman, K. Tai, O. Beckstein, M. Sansom, and D. Beeson. (2012). A novel congenital myasthenic syndrome due to decreased acetylcholine receptor ion-channel conductance. Brain 135: 1070-1080. 22382357
Witzemann, V., E. Stein, B. Barg, T. Konno, M. Koenen, W. Kues, M. Criado, M. Hofmann, and B. Sakmann. (1990). Primary structure and functional expression of the α-, β-, γ-, δ- and ε-subunits of the acetylcholine receptor from rat muscle. Eur J Biochem 194: 437-448. 1702709
Xiong, W., X. Wu, D.M. Lovinger, and L. Zhang. (2012). A common molecular basis for exogenous and endogenous cannabinoid potentiation of glycine receptors. J. Neurosci. 32: 5200-5208. 22496565
Xue, H. (1998). Identification of major phylogenetic branches of inhibitory ligand-gated channel receptors. J. Mol. Evol. 47: 323-333. 9732459
Yamaguchi, M., Y. Sawa, K. Matsuda, F. Ozoe, and Y. Ozoe. (2012). Amino acid residues of both the extracellular and transmembrane domains influence binding of the antiparasitic agent milbemycin to Haemonchus contortus AVR-14B glutamate-gated chloride channels. Biochem. Biophys. Res. Commun. 419: 562-566. 22369940
Yévenes, G.E. and H.U. Zeilhofer. (2011). Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids. PLoS One 6: e23886. 21901142
Yu, X., M. Wang, M. Kang, L. Liu, X. Guo, and B. Xu. (2011). Molecular cloning and characterization of two nicotinic acetylcholine receptor β subunit genes from Apis cerana cerana. Arch Insect Biochem Physiol 77: 163-178. 21618599
Zemkova, H., V. Tvrdonova, A. Bhattacharya, and M. Jindrichova. (2014). Allosteric modulation of ligand gated ion channels by ivermectin. Physiol Res 63Suppl1: S215-224. 24564661
Zhu, F. and G. Hummer. (2009). Gating transition of pentameric ligand-gated ion channels. Biophys. J. 97: 2456-2463. 19883588
Zhu, F. and G. Hummer. (2010). Pore opening and closing of a pentameric ligand-gated ion channel. Proc. Natl. Acad. Sci. USA 107: 19814-19819. 21041674
Zuo, H., L. Gao, Z. Hu, H. Liu, and G. Zhong. (2013). Cloning, expression analysis, and molecular modeling of the γ-aminobutyric acid receptor alpha2 subunit gene from the common cutworm, Spodoptera litura. J Insect Sci 13: 49. 23909412