LIGAND‐GATED ION CHANNELS
2011; Wiley; Volume: 164; Issue: s1 Linguagem: Inglês
10.1111/j.1476-5381.2011.01649_4.x
ISSN1476-5381
AutoresS P H Alexander, Alistair Mathie, JA Peters,
Tópico(s)Receptor Mechanisms and Signaling
ResumoLigand-gated ion channels (LGICs) are integral membrane proteins that contain a pore which allows the regulated flow of selected ions across the plasma membrane. Ion flux is passive and driven by the electrochemical gradient for the permeant ions. The channels are opened, or gated, by the binding of a neurotransmitter to an orthosteric site(s) that triggers a conformational change that results in the conducting state. Modulation of gating can occur by the binding of endogenous, or exogenous, modulators to allosteric sites. LGICs mediate fast synaptic transmission, on a millisecond time scale, in the nervous system and at the somatic neuromuscular junction. Such transmission involves the release of a neurotransmitter from a pre-synaptic neurone and the subsequent activation of post-synaptically located receptors that mediate a rapid, phasic, electrical signal (the excitatory, or inhibitory, post-synaptic potential). However, In addition to their traditional role in phasic neurotransmission, it is now established that some LGICs mediate a tonic form of neuronal regulation that results from the activation of extra-synaptic receptors by ambient levels of neurotransmitter. 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; Changeux, 2010), 5-HT3 (Barnes et al., 2009; Walstab et al., 2010), ionotropic glutamate (Lodge, 2009; Traynelis et al., 2010) and P2X receptors (Jarvis and Khakh, 2009; Surprenant and North, 2009) and the inhibitory, anion-selective, GABAA (Olsen and Sieghart, 2008; Belelli et al., 2009) and glycine receptors (Lynch, 2009; Yevenes and Zeilhofer, 2011). 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 (Miller and Smart, 2010; Thompson et al., 2010). 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. Barnes NM, Hales TG, Lummis SCR, Peters JA (2009). The 5-HT3 receptor – the relationship between structure and function. Neuropharmacology56: 273–284. Belelli D, Harrison NL, Maguire J, Macdonald RL, Walker MC, Cope DW (2009). Extrasynaptic GABAA receptors: form, pharmacology, and function. J Neurosci29: 12757–12763. Changeux J-P (2010). Allosteric receptors: from electric organ to cognition. Annu Rev Pharmacol Toxicol50: 1–38. 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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., 2010)] 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 characterised 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; Walstab et al., 2010a). 5-HT3A, -C, -D, and -E subunits also interact with the chaperone RIC-3 which predominantly enhances the surface expression of homomeric 5-HT3A receptor (Walstab et al., 2010a). The co-expression of 5-HT3A and 5-HT3C-E subunits has been demonstrated in human colon (Kapeller et al., 2011). 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), but this is inconsistent with recent reports which show at least one A-A interface (Lochner and Lummis, 2010; Thompson et al., 2011b). 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), influences the potency of channel blockers, 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) which may be explained by the orthosteric binding site residing at an interface formed between 5-HT3A subunits (Lochner and Lummis, 2010; Thompson et al., 2011b). 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 alternative splicing of the genes HTR3A and E (Hope et al., 1993; Bruss et al., 2000; Niesler et al., 2007, 2008; Niesler 2011). In addition, the use of tissue-specific promoters driving expression from different transcriptional start sites has been reported for the HTR3A, HTR3B, HTR3D and HTR3E genes, which could result in 5-HT3 subunits harbouring different N-termini (Tzvetkov et al., 2007; Jensen et al., 2008; Niesler, 2011). To date, inclusion of the 5-HT3A subunit appears imperative for 5-HT3 receptor function. 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). Similarly, TMB-8, diltiazem, picrotoxin, bilobalide and ginkgolide B are not selective for 5-HT3 receptors (e.g. Thompson et al., 2011a). The anti-malarial drugs mefloquine and quinine exert a modestly more potent block of 5-HT3A versus 5-HT3AB receptor-mediated responses (Thompson and Lummis, 2008). Varenicline, know better as a partial agonist of nicotinic acetylcholine α4β2 receptors, is also an agonist of the 5-HT3A receptor (Lummis et al. 2011). 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; Thompson and Lummis, 2006, 2007; Walstab et al., 2010b). 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; SR57227A, 4-amino-(6-chloro-2-pyridyl)-1 piperidine hydrochloride, TMB-8, 8-(diethylamine)octyl-3,4,5-trimethoxybenzoate 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. 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. 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 Rev: 46, 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. Machu TK (2011). Therapeutics of 5-HT3 receptor antagonists: current uses and future directions. Pharmacol Ther130: 338–347. Modica MN, Pittalà V, Romeo G, Salerno L, Siracusa MA (2010). Serotonin 5-HT3 and 5-HT4 ligands: an update of medicinal chemistry research in the last few years. Curr Med Chem17: 334–362. Niesler B (2011). 5-HT3 receptors: potential of individual isoforms for personalised therapy.Curr Opin Pharmacol11: 81–86. 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 Pharmacol Sci26: 587–594. Peters JA, Barnes NM, Hales TG, Lummis SCR (2010). 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. Thompson AJ, Lester HA, Lummis SCR (2010). The structural basis of function in Cys-loop receptors. Q Rev Biophys43: 449–499. Walstab J, Rappold G, Niesler B (2010b). 5-HT3 receptors: role in disease and target of drugs. Pharmacol Ther128: 146–169. Yaakob N, Malone DT, Exintaris B, Irving HR (2011). Heterogeneity amongst 5-HT3 receptor subunits: is this significant? Curr Mol Med11: 57–68. Overview: Nicotinic acetylcholine receptors are members of the Cys-loop family of transmitter-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; Taly et al., 2009, Wu and Lukas, 2011). All nicotinic receptors are pentamers in which each of the five subunits contains four α-helical transmembrane domains. Genes (Ensembl family ID ENSF00000000049) encoding a total of 17 subunits (α1-10, β1-4, γ, δ and ε) have been identified (Kalamida et al., 2007). All subunits with the exception of α8 (present in avian species) have been identified in mammals. 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 orthosteric 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). nAChRs contain several allosteric modulatory sites. One such site, for positive allosteric modulators (PAMs) and allosteric agonists, has been proposed to reside within an intrasubunit cavity between the four transmembrane domains (Young et al., 2008; Gill et al., 2011; see also Hibbs and Gouaux, 2011). 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 orthosteric 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)2β1δε, 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] which 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 subunit to constitute a hetero-oligomeric assembly (e.g., α7β2 and α9α10). 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). In addition, numerous proteins interact with nicotinic ACh receptors modifying their assembly, trafficking to and from the cell surface, and activation by ACh (reviewed by Millar, 2008; Araud et al., 2010; Jones et al., 2010). The nicotinic receptor subcommittee of NC-IUPHAR has recommended a nomenclature and classification scheme for nicotinic acetylcholine (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). Commonly used agonists of nicotinic acetylcholine 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 summarised 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-Noriaga et al., (1997), Papke et al. (2001, 2008), Paul et al. (2002) and Wu et al. (2006). Type I PAMs increase peak agonist-evoked responses but have little, or no, effect on the rate of desensitization of α7 nicotinic ACh receptors whereas type II PAMs also cause a large reduction in desensitization (reviewed by Williams et al., 2011). Abbreviations: 4BP-TQS, 4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide; 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; AZ11637326, (5′-(2-fluoro[3,4,5(-3)H3]phenyl)-spiro[1-azabicyclo [2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine, DHβE, dihydro-β-erythroidine; DMPP, 1,1-dimethyl-4-phenylpiperazinium; JNJ-1930942, 2-[[4-fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol; LY-2087101, see Broad et al. (2006) for structure; NS1738, 1-(5-chloro-2-hydroxy-phenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)-urea; NS9283, 3-(3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile; 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-282987N-[(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 Albuquerque EX, Pereira EF, Alkondon M, Rogers SW (2009). Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev89: 73–120. 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Wu J, Lukas RJ (2011). Naturally expressed nicotinic acetylcholine receptor subtypes. Biochem Pharmacol82: 800–807. Zouridakis M, Zisimopoulou P, Poulas K, Tzartos SJ (2009). Recent advances in understanding the structure of nicotinic acetylcholine receptors. IUBMB Life61: 407–423. Overview: The GABAA receptor is a ligand-gated ion channel of the Cys-loop family that includes the nicotinic acetylcholine, 5-HT3 and strychnine-sensitive glycine receptors. GABAA receptor-mediated inhibition within the CNS occurs by fast synaptic transmission, sustained tonic inhibition and temporally intermediate events that have been termed ‘GABAA, slow’ (Campogna and Pearce, 2011). GABAA receptors exist as pentamers of 4TM subunits that form an intrinsic anion selective channel. Sequences of six α, three β, three γ, one δ, three ρ, one ε, one π and one θ GABAA receptor subunits (Ensembl gene family ID ENSF00000000053) have been reported in mammals (Korpi et al., 2002; Whiting, 2003; Sieghart, 2006; Olsen and Sieghart, 2008, 2009). The π-subunit is restricted to reproductive tissue. Alternatively spliced versions of many subunits exist (e.g.α4- and α6- (both not functional) α5-, β2-, β3- and γ2), along with RNA editing of the α3 subunit (Daniel and Ohman, 2009). The three ρ-subunits, (ρ1-3) function as either homo- or hetero-oligomeric assemblies (Zhang et al., 2001; Chebib, 2004). Receptors formed from ρ-subunits, because of their distinctive pharmacology that includes insensitivity to bicuculline, benzodiazepines and barbiturates, have sometimes been termed GABAC receptors (Zhang et al., 2001), but they are classified as GABAA receptors by NC-IUPHAR on the basis of structural and functional criteria (Barnard et al., 1998; Olsen and Sieghart, 2008, 2009). Many GABAA receptor subtypes contain α-, β- and γ-subunits with the likely stoichiometry 2α.2β.1γ (Korpi et al., 2002, Olsen and Sieghart, 2008). It is thought that the majority of GABAA receptors harbour a single type of α- and β-subunit variant. The α1β2γ2 hetero-oligomer constitutes the largest population of GABAA receptors in the CNS, followed by the α2β3γ2 and α3β3γ2 isoforms. Receptors that incorporate the α4- α5-or α6-subunit, or the β1-, γ1-, γ3-, δ-, ε- and θ-subunits, are less numerous, but they may nonetheless serve important functions. For example, extrasynaptically located receptors that contain α6- and δ-subunits in cerebellar granule cells, or an α4- and δ-subunit in dentate gyrus granule cells and thalamic neurones, mediate a tonic current that is important for neuronal excitability in response to ambient concentrations of GABA (see Mody and Pearce, 2004; Semyanov et al., 2004; Farrant and Nusser, 2005; Belelli et al., 2009). GABA binding occurs at the β+/α- subunit interface and the homologous γ+/α- subunits interface creates the benzodiazepine site. A second site for benzodiazepine binding has recently been postulated to occur at the α+/β- interface (Ramerstorfer et al., 2011; reviewed by Sigel and Lüscher, 2011). The particular α-and γ-subunit isoforms exhibit marked effects on recognition and/or efficacy at the benzodiazepine site. Thus, receptors incorporating either α4- or α6-subunits are not recognised by ‘classical’ benzodiazepines, such as flunitrazepam (but see You et al., 2010). The trafficking, cell surface expression, internalisation and function of GABAA receptors and their subunits are discussed in detail in several recent reviews (Chen and Olsen, 2007; Jacob et al., 2008; Lüscher et al., 2011; Vithlani et al., 2011) but one point worthy of note is that receptors incorporating the γ2 subunit (except when associated wi
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