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• W4235277233 abstract "British Journal of PharmacologyVolume 158, Issue s1 p. S103-S121 Free Access LGIC First published: 13 November 2009 https://doi.org/10.1111/j.1476-5381.2009.00502.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat LGIC Overview: Ligand-gated ion channels (LGICs) are integral membrane proteins that contain a pore that allows the regulated flow of selected ions across the plasma membrane. The channels are opened, or gated, by the binding of a neurotransmitter that triggers a conformational change that results in the conducting state. LGICs mediate fast synaptic transmission, on a millisecond time scale, in the nervous system and at the somatic neuromuscular junction, but the expression of some LGICs by non-excitable cells is suggestive of additional functions. By convention, the LGICs comprise the excitatory, cation-selective, nicotinic acetylcholine (Millar and Gotti, 2009), 5-HT3 (Barnes et al., 2009), ionotropic glutamate (Lodge, 2009) and P2X receptors (Jarvis and Khakh, 2009) and the inhibitory, anion-selective, GABAA (Olsen and Sieghart, 2008) and glycine receptors (Lynch, 2009). The nicotinic acetylcholine, 5-HT3, GABAA and glycine receptors (and an additional zinc-activated channel) are pentameric structures and are frequently referred to as the Cys-loop receptors due to the presence of a defining loop of residues formed by a disulphide bond in the extracellular domain of their constituent subunits. However, the prokaryotic ancestors of these receptors contain no such loop, and the term pentameric ligand-gated ion channel (pLGIC) is gaining acceptance in the literature (Hilf and Dutzler, 2009). The ionotropic glutamate and P2X receptors are tetrameric and trimeric structures respectively. Multiple genes encode the subunits of LGICs, and the majority of these receptors are heteromultimers. Such combinational diversity results within each class of LGIC in a wide range of receptors with differing pharmacological and biophysical properties and varying patterns of expression within the nervous system and other tissues. The LGICs thus present attractive targets for new therapeutic agents with improved discrimination between receptor isoforms and a reduced propensity for off-target effects. The development of novel, faster screening techniques for compounds acting on LGIcs (Dunlop et al., 2008) will greatly aid in the development of such agents. Further Reading Barnes NM, Hales TG, Lummis SCR, Peters JA (2009). The 5-HT3 receptor – the relationship between structure and function. Neuropharmacology 56: 273– 284. Dunlop J, Bowlby M, Peri R, Vasilyev D, Arias R (2008). High-throughput electrophysiology: an emerging paradigm for ion channel screening and physiology. Nat Rev Drug Discov 7: 358– 368. Hilf RJ, Dutzler R (2009). A prokaryotic perspective on pentameric ligand-gated ion channel structure. Curr Opin Struct Biol 19: 418– 424. Jarvis MF, Khakh BS (2009). ATP-gated P2X cation-channels. Neuropharmacology 56: 230– 236. Lodge D (2009). The history of the pharmacology and cloning of ionotropic glutamate receptors and the development of idiosyncratic nomenclure. Neuropharmacology 56: 6– 21. Lynch JW (2009). Native glycine receptors and their physiological roles. Neurpharmacology 56: 303– 309. Millar NS, Gotti C (2009). Diversity of vertebrate nicotinic acetylcholine receptors. Neuropharmacology 56: 237– 246. Olsen RW, Sieghart W (2008). International Union of Pharmacology. LXX. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev 60: 243– 260. 5-HT3 (5-hydroxytryptamine3) Overview: The 5-HT3 receptor [nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-hydroxytryptamine (serotonin) receptors (Hoyer et al., 1994; see also Peters et al., 2009)] is a ligand-gated ion channel of the Cys-loop family that includes the nicotinic acetylcholine, GABAA and strychnine-sensitive glycine receptors. The receptor exists as a pentamer of 4TM subunits that form an intrinsic cation-selective channel (Barnes et al., 2009). Five human 5-HT3 receptor subunits have been cloned, and homo-oligomeric assemblies of 5-HT3A and hetero-oligomeric assemblies of 5-HT3A and 5-HT3B subunits have been characterized in detail. The 5-HT3C (ENSG00000178084), 5-HT3D (ENSG00000186090) and 5-HT3E (ENSG00000186038) subunits (Karnovsky et al., 2003; Niesler et al., 2003), like the 5-HT3B subunit, do not form functional homomers, but are reported to assemble with the 5-HT3A subunit to influence its functional expression rather than pharmacological profile (Niesler et al., 2007; Holbrook et al., 2009). A recombinant hetero-oligomeric 5-HT3AB receptor has been reported to contain two copies of the 5-HT3A subunit and three copies of the 5-HT3B subunit in the order B-B-A-B-A (Barrera et al., 2005). The 5-HT3B subunit imparts distinctive biophysical properties upon hetero-oligomeric 5-HT3AB versus homo-oligomeric 5-HT3A recombinant receptors (Davies et al., 1999; Dubin et al., 1999; Hanna et al., 2000; Kelley et al., 2003; Stewart et al., 2003; Peters et al., 2005; Jensen et al., 2008), but generally has only a modest effect upon the apparent affinity of agonists, or the affinity of antagonists (Brady et al., 2001; but see Dubin et al., 1999; Das and Dillon, 2003; Deeb et al., 2009). However, 5-HT3A and 5-HT3AB receptors differ in their allosteric regulation by some general anaesthetic agents, small alcohols and indoles (Solt et al., 2005; Rüsch et al., 2007; Hu and Peoples, 2008). The potential diversity of 5-HT3 receptors is increased by alternatively spliced variants of the 5-HT3A and 5-HT3E subunits (Hope et al., 1993; Bruss et al., 2000; Niesler et al., 2007; 2008), and tissue-specific preferences for different transcription start sites in the HTR3B gene, which could result in three different 5-HT3B subunit N-termini (Tzvetkov et al., 2007; Jensen et al., 2008). To date, inclusion of the 5-HT3A subunit appears imperative for 5-HT3 receptor function. Nomenclature 5-HT3 Former names M Ensembl ID 5-HT3A ENSG00000166736, 5-HT3B ENSG00000149305 Selective agonists (pEC50) 3-Chlorophenyl-biguanide (5.4–5.8), 2-methyl-5-HT (5.5–5.6), 1-phenylbiguanide (4.1) Selective antagonists (pKi) (S)-Zacopride (9.0), granisetron (8.6–8.8), tropisetron (8.5–8.8), ondansetron (7.8–8.3) Channel blockers Diltiazem, TMB-8, picrotoxin (+5-HT3B potency reduced, Das and Dillon (2003)) Radioligands (KD) [3H]Ramosetron (0.15 nM), [3H]granisetron (1.2 nM), [3H]-(S)-zacopride (2.0 nM), [3H]GR65630 (2.6 nM), [3H]LY278584 (3 nM) Functional characteristics γ= 0.4–0.8 pS (+5-HT3B, γ= 16 pS); inwardly rectifying current (+5-HT3B, rectification reduced); nH 2-3 (+5-HT3B 1-2); relative permeability to divalent cations reduced by co-expression of the 5-HT3B subunit Quantitative data in the table refer to homo-oligomeric assemblies of the human 5-HT3A subunit, or the receptor native to human tissues. Significant changes introduced by co-expression of the 5-HT3B subunit are indicated in parenthesis. Methadone, although not a selective antagonist, displays multimodal and subunit-dependent antagonism of 5-HT3 receptors (Deeb et al., 2009). Human (Belelli et al., 1995; Miyake et al., 1995), rat (Isenberg et al., 1993), mouse (Maricq et al., 1991), guinea-pig (Lankiewicz et al., 1998), ferret (Mochizuki et al., 2000) and canine (Jensen et al., 2006) orthologues of the 5-HT3A receptor subunit have been cloned that exhibit intraspecies variations in receptor pharmacology. Notably, most ligands display significantly reduced affinities at the guinea-pig 5-HT3 receptor in comparison with other species. In addition to the agents listed in the table, native and recombinant 5-HT3 receptors are subject to allosteric modulation by extracellular divalent cations, alcohols, several general anaesthetics and 5-hydroxy- and halide-substituted indoles (see reviews by Parker et al., 1996; Davies et al., 2006; Thompson and Lummis, 2006; 2007). Abbreviations: GR65630, 3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone; LY278584, 1-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole- 3-carboxamide; TMB-8, 8-(diethylamine)octyl-3,4,5-trimethoxybenzoate Further Reading Barnes NM, Hales TG, Lummis SCR, Peters JA (2009). The 5-HT3 receptor – the relationship between structure and function. Neuropharmacology56: 273–284. Chameau P, Van Hooft JA (2006). Serotonin 5-HT3 receptors in the central nervous system. Cell Tissue Res326: 573–581. Costall B, Naylor RJ (2004). 5-HT3 receptors. Curr Drug Targets CNS Neurol Disord3: 27–37. Davies DL, Asatryan L, Kuo ST, Woodward JJ, King BF, Alkana RL et al. (2006). Effects of ethanol on adenosine 5′-triphosphate-gated purinergic and 5-hydroxytryptamine receptors. Alcohol Clin Exp Res30: 349–358. Engleman EA, Rodd ZA, Bell RL, Murphy JM (2008). The role of 5-HT3 receptors in drug abuse and as a target for pharmacotherapy. CNS Neurol Disord Drug Targets7: 454–467. Faerber L, Drechsler S, Ladenburger S, Gschaidmeier H, Fischer W (2007). The neuronal 5-HT3 receptor network after 20 years of research – evolving concepts in management of pain and inflammation. Eur J Pharmacol560: 1–8. Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ et al. (1994). International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev46: 157–203. Jensen AA, Davies PA, Bräuner-Osborne H, Krzywkowski K (2008). 3B but which 3B? And that's just one of the questions: the heterogeneity of human 5-HT3 receptors. Trends Pharmacol Sci29: 437–444. Niesler B, Kapeller J, Hammer C, Rappold G (2008). Serotonin type 3 receptor genes: HTR3A, B, C, D, E. Pharmacogenomics9: 501–514. Parker RM, Bentley KR, Barnes NM (1996). Allosteric modulation of 5-HT3 receptors: focus on alcohols and anaesthetic agents. Trends Pharmacol Sci17: 95–99. Peters JA, Hales TG, Lambert JJ (2005). Molecular determinants of single channel conductance and ion selectivity in the Cys-loop transmitter-gated ion channels: insights from the 5-HT3 receptor. Trends Pharmaco Sci26: 587–594. Peters JA, Barnes NM, Hales TG, Lummis SCR (2009). 5-HT3 receptors, introductory chapter. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/IC/FamilyIntroductionForward?familyId=2 Thompson AJ, Lummis SCR (2006). 5-HT3 receptors. Curr Pharm Des12: 3615–3630. Thompson AJ, Lummis SCR (2007). The 5-HT3 receptor as a therapeutic target. Expert Opin Ther Targets11: 527–540. Reeves DC, Lummis SCR (2002). The molecular basis of the structure and function of the 5-HT3 receptor: a model ligand-gated ion channel. Mol Membr Biol19: 11–26. References Barrera NP et al. (2005). Proc Natl Acad Sci USA 102: 12595– 12600. Belelli D et al. (1995). Mol Pharmacol 48: 1054– 1062. Brady CA et al. (2001). Neuropharmacology 41: 282– 284. Bruss M et al. (2000). Naunyn Schmiedebergs Arch Pharmacol 362: 392– 401. Das P, Dillon GH (2003). Brain Res Mol Brain Res 119: 207– 212. Davies PA et al. (1999). Nature 397: 359– 363. Deeb TZ et al. (2009). Mol Pharmacol 75: 908– 917. Dubin A et al. (1999). J Biol Chem 274: 30799– 30810. Hanna MC et al. (2000). J Neurochem 75: 240– 247. Hope AG et al. (1993). Eur J Pharmacol 245: 187– 192. Holbrook JD et al. (2009). J Neurochem 108: 384– 396. Hu XQ, Peoples RW (2008). J Biol Chem 283: 6826– 6831. Isenberg KE et al. (1993). Neuroreport 18: 121– 124. Jensen TN et al. (2006). Eur J Pharmacol 538: 23– 31. Karnovsky AM et al. (2003). Gene 319: 137– 148. Kelley SP et al. (2003). Nature 424: 321– 324. Lankiewicz S et al. (1998). Mol Pharmacol 53: 202– 212. Maricq AV et al. (1991). Science 254: 432– 437. Miyake A et al. (1995). Mol Pharmacol 48: 407– 416. Mochizuki S et al. (2000). Eur J Pharmacol 399: 97– 106. Niesler B et al. (2003). Gene 310: 101– 111. Niesler B et al. (2007). Mol Pharmacol 72: 8– 17. Rüsch D et al. (2007). J Pharmacol Exp Ther 321: 1069– 1074. Solt K et al. (2005). J Pharmacol Exp Ther 315: 771– 776. Stewart A et al. (2003). Neuropharmacology 44: 214– 223. Tzvetkov MV et al. (2007). Gene 386: 52– 62. Acetylcholine (nicotinic) Nicotinic acetylcholine (nACh) receptors are members of the Cys-loop family of ligand-gated ion channels that includes the GABAA, strychnine-sensitive glycine and 5-HT3 receptors (Sine and Engel, 2006; Albuquerque et al., 2009; Millar and Gotti, 2009). All nicotinic receptors are pentamers of 4TM subunits. Genes (Ensembl family ID ENSF00000000049) encoding a total of 17 subunits (α1–10, β1–4, δ, ε and γ) have been identified (Kalamida et al., 2007). All subunits with the exception of avian α8 have been identified in mammalian species. All α subunits possess two tandem cysteine residues near to the site involved in acetylcholine binding, and subunits not named α lack these residues (Millar and Gotti, 2009). The ligand binding site is formed by residues within at least three peptide domains on the α subunit (principal component), and three on the adjacent subunit (complementary component). The high resolution crystal structure of the molluscan acetylcholine binding protein, a structural homologue of the extracellular binding domain of a nicotinic receptor pentamer, in complex with several nicotinic receptor ligands (e.g. Celie et al., 2004) and the crystal structure of the extracellular domain of the α1 subunit bound to α-bungarotoxin at 1.94 Å resolution (Dellisanti et al., 2007), has revealed the binding site in detail (reviewed Sine and Engel, 2006; Kalamida et al., 2007; Changeux and Taly, 2008; Rucktooa et al., 2009). Nicotinic receptors at the somatic neuromuscular junction of adult animals have the stoichiometry (α1)2β1εδ, whereas an extrajunctional (α1)2β1γδ receptor predominates in embryonic and denervated skeletal muscle and other pathological states. Other nicotinic receptors are assembled as combinations of α(2–6) and β(2–4) subunits. For α2, α3, α4 and β2 and β4 subunits, pairwise combinations of α and β (e.g. α3β4, α4β2) are sufficient to form a functional receptor in vitro, but far more complex isoforms may exist in vivo (reviewed by Gotti et al., 2006; 2009, Millar and Gotti, 2009). There is strong evidence that the pairwise assembly of some α and β subunits can occur with variable stoichiometry [e.g. (α4)2(β2)2, or (α4)3(β2)2] that influences the biophysical and pharmacological properties of the receptor (Millar and Gotti, 2009). α5 and β3 subunits lack function when expressed alone, or pairwise, but participate in the formation of functional hetero-oligomeric receptors when expressed as a third subunit with another α and β pair [e.g. α4α5αβ2, α4αβ2β3, α5α6β2, see Millar and Gotti (2009) for further examples]. The α6 subunit can form a functional receptor when co-expressed with β4 in vitro, but more efficient expression ensues from incorporation of a third partner, such as β3 (Yang et al., 2009). The α7, α8 and α9 subunits form functional homo-oligomers, but can also combine with a second α subunit to constitute a hetero-oligomeric assembly (e.g. α9α10). A functional assembly of α7 and β2 subunits has additionally been reported (Khiroug et al., 2002). For functional expression of the α10 subunit, co-assembly with α9 is necessary. The latter, along with the α10 subunit, appears to be largely confined to cochlear and vestibular hair cells. Comprehensive listings of nicotinic receptor subunit combinations identified from recombinant expression systems, or in vivo, are given in Millar and Gotti (2009). The nicotinic receptor subcommittee of NC-IUPHAR has recommended a nomenclature and classification scheme for nACh receptors based on the subunit composition of known, naturally and/or heterologously expressed nACh receptor subtypes (Lukas et al., 1999). Headings for this table reflect abbreviations designating nACh receptor subtypes based on the predominant α subunit contained in that receptor subtype. An asterisk following the indicated α subunit denotes that other subunits are known to, or may, assemble with the indicated α subunit to form the designated nACh receptor subtype(s). Where subunit stoichiometries within a specific nACh receptor subtype are known, numbers of a particular subunit larger than 1 are indicated by a subscript following the subunit (enclosed in parentheses – see also Collingridge et al., 2009). Nomenclature α1* α2* α3* Previous names Muscle-type, muscle – Autonomic, ganglionic Selective agonists Succinylcholine [selective for (α1)2β1γδ)] – – Positive allosteric modulators – α2β4: LY-2087101 (Broad et al. (2006) – Selective antagonists Waglerin-1 [selective for α(1)2β1εδ], α-bungarotoxin, α-conotoxin GI, α-conotoxin MI, pancuronium – α3β2: α-conotoxin MII (also blocks α6-containing), α-conotoxin-GIC, α-conotoxin PnIA, α-conotoxin TxIAα3β4: α-conotoxin AuIB Commonly used antagonists (α1)2β1γδ and (α1)2β1εδ: α-bungarotoxin > pancuronium > vecuronium > rocuronium > (+)-Tc (IC50= 43–82 nM) α2β2: DHβE (KB= 0.9 µM), (+)-Tc (KB= 1.4 µM)α2β4: DHβE (KB= 3.6 µM), (+)-Tc (KB= 4.2 µM) α3β2: DHβE (KB= 1.6 µM, IC50= 2.0 µM), (+)-Tc (KB= 2.4 µM)α3β4: DHβE (KB= 19 µM, IC50= 26 µM), (+)-Tc (KB= 2.2 µM) Channel blockers α(1)2β1εδ and α(1)2β1yδ: gallamine (IC50 ∼ 1 µM)α(1)2β1εδ: mecamylamine (IC50 ∼ 1.5 µM) Mecamylamine, hexamethonium α3β2: mecamylamine (IC50= 7.6 µM), hexamethoniumα3β4: mecamylamine (IC50= 0.39 µM),hexamethonium Radioligands (Kd) [3H]/[125I]-α-bungarotoxin [3H]/[125I]-epibatidine (hα2β4, 42 pM; rα2β2, 10–21 pM; rα2β4, 84–87 pM), [3H]-cytisine [3H]/[125I]-epibatidine (hα3β2, 7 pM; hα3β4, 230 pM; rα3β2, 14–34 pM, rα3β4, 290–304 pM), [3H]-cytisine Functional characteristics α(1)2βγδ: PCa/PNa= 0.16–0.2, Pf= 2.1–2.9%; α(1)2βεδ: PCa/PNa= 0.65–1.38, Pf= 4.1–7.2% α2β2: PCa/PNa ∼ 1.5 α3β2: PCa/PNa= 1.5; α3β4: PCa/PNa= 0.78–1.1, Pf= 2.7–4.6% Nomenclature α4* α6* α7* Previous names Neuronal, α-bungarotoxin-insensitive – Neuronal, α-bungarotoxin-sensitive Selective agonists α4β2: TC-2559 (Chen et al., 2003), TC-2403 (RJR-2403, Papke et al., 2000) – (α7)5: PNU-282987 (Bodnar et al., 2005), PHA-543613 (Wishka et al., 2006); PHA-709829 (Acker et al., 2008), A-582941 (Bitner et al., 2007), TC-5619 (Hauser et al., 2009) Positive allosteric modulators α4β2 and α4β4: LY-2087101 (Broad et al. (2006) – (α7)5:Type 1: LY-2087101 (Broad et al., 2006), NS1738 (Timmermann et al., 2007)(α7)5:Type 2: PNU-120596 (Hurst et al., 2005), A-867744 (Malysz et al., 2009) Selective antagonists – α6/α3β2β3 chimera: α-conotoxin PIAα6β2β3: α-conotoxin MII [H9A, L15A]α6β2*: α-conotoxin MII (also blocks α3β2) (α7)5: α-bungarotoxin, methyllycaconitine, α-conotoxin ImI, α-conotoxin ArIB Commonly used antagonists α4β2: DHβE (KB= 0.1 µM, IC50= 0.08–0.9 µM), (+)-Tc (KB= 3.2 µM, IC50= 34 µM)α4β4: DHβE (KB= 0.01 µM, IC50= 0.19–1.2 µM), (+)-Tc (KB= 0.2 µM, IC50= 50 µM) α6/α3β2β3 chimera: DHβE (IC50= 1.1 µM) (α7)5: DHβE (IC50= 8–20 µM)(α7)5: (+)-Tc (IC50= 3.1 µM) Channel blockers α4β2: mecamylamine (IC50= 3.6–4.1 µM), hexamethonium (IC50= 6.8–29 µM)α4β4: mecamylamine (IC50= 0.33–4.9 µM), hexamethonium (IC50= 91 µM) α6/α3β2β3 chimera: mecamylamine (IC50= 11 µM), hexamethonium (α7)5: mecamylamine (IC50= 15.6 µM) Radioligands (Kd) [3H]/[125I]-epibatidine (hα4β2, 10–33 pM; hα4β4, 187 pM; rα4β2, 30–46 pM; rα4β4, 85–94 pM), [3H]-cytisine (hα4β2, 430–630 pM; rα4β2, 100 pM; hα4β4 100 pM), [3H]-nicotine (rα4β2, 400 pM) [3H]-epibatidine (native cα6β4*, 35 pM), [125I]-α-conotoxin MII [3H]-epibatidine ((hα7)5, 0.6 pM)[3H]/[125I]-α-bungarotoxin ((hα7)5, 0.7–5 nM), [3H]-methyllycaconitine (native rα7*, 1.9 nM), [3H]-A-585539 (native hα7, 70 pM; Anderson et al., 2008) Functional characteristics α4β2: PCa/PNa= 1.65, Pf= 2.6–2.9%; α4β4: Pf= 1.5–3.0 % – PCa/PNa= 6.6–20, Pf= 8.8–11.4% Nomenclature α8* (avian) α9* Previous names Neuronal, α-bungarotoxin-sensitive – Selective agonists – – Selective antagonists – (α9)5: α-bungarotoxin, strychnine, nicotine, muscarineα9α10: α-contoxin RgIA, α-bungarotoxin, strychnine, nicotine, muscarine Commonly used antagonists (α8)5: α-bungarotoxin > atropine ≥ (+)-Tc ≥ strychnine (α9)5: α-bungarotoxin > methyllycaconitine > strychnine ∼ tropisetron > (+)-Tcα9α10: α-bungarotoxin > tropisetron = strychnine > (+)-Tc Channel blockers – – Radioligands (Kd) [3H]-epibatidine ((α8)5, 0.2 nM)[3H]/[125I]-α-bungarotoxin (native α8*, 5.5 nM) [3H]-methyllycaconitine (hα9α10, 7.5 nM)[3H]/[125I]-α-bungarotoxin Functional characteristics – (α9)5: PCa/PNa= 9; α9α10: PCa/PNa= 9, Pf= 22% Commonly used agonists of nACh receptors that display limited discrimination in functional assays between receptor subtypes include A-85380, cytisine, DMPP, epibatidine, nicotine and the natural transmitter, ACh. A summary of their profile across differing receptors is provided in Gotti et al. (2006) and quantitative data across numerous assay systems are summarized in Jensen et al. (2005). Quantitative data presented in the table for commonly used antagonists and channel blockers for human receptors studied under voltage-clamp are from Buisson et al. (1996), Chavez-Noriega et al. (1997), Papke et al. (2001; 2008), Paul et al. (2002) and Wu et al. (2006). Abbreviations: A-582941, 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole; A-585539, (1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azaniabicyclo[2.2.1]heptane; A-867744, 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide; ABT-594, (R)-5-(2-azetidinylmethoxy)-2-chloropyridine; ACh, acetylcholine; DHβE, dihydro-β-erythroidine; DMPP, 1,1-dimethyl-4-phenylpiperazinium; LY-2087101, see Broad et al. (2006) for structure; NS1738, 1-(5-chloro-2-hydroxy-phenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)-urea; PHA-543613, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide; PHA-709829, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide; PNU-120596, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea; PNU-282987, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride; PSAB-OFP, (R)-(-)-5′phenylspiro[1-azabicyclo[2.2.2] octane-3,2′-(3′H)furo[2,3-b]pyridine; TC-2403, (RJR-2403), (E)-N-methyl-4-(3-pyridinyl)-3-butene-1-amine; TC-2559, (E)-N-methyl-4-[3-(5-ethoxypyridin)yl]-3-buten-1-amine; TC-5619, N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide; (+)-Tc, (+)-tubocurarine Additional Reading Albuquerque EX, Pereira EF, Alkondon M, Rogers SW (2009). Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev89: 73–120. Arneric SP, Holladay M, Williams M (2007). 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