Nicotinic Acetylcholine Receptor Structure
Published by Anonymous on 2007/9/30 (6225 reads)
1: Anat Rec A Discov Mol Cell Evol Biol. 2006 Apr;288(4):424-34.
Nicotinic acetylcholine receptor structure and function in the efferent auditory system.
Lustig LR.
Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, California 941430, USA. llustig@ohns.ucsf.edu
This article reviews and presents new data regarding the nicotinic acetylcholine receptor subunits alpha9 and alpha10. Although phylogentically ancient, these subunits have only recently been identified as critical components of the efferent auditory system and medial olivocochlear pathway. This pathway is important in auditory processing by modulating outer hair cell function to broadly tune the cochlea and improve signal detection in noise. Pharmacologic properties of the functionally expressed alpha9alpha10 receptor closely resemble the cholinergic response of outer hair cells. Molecular, immunohistochemical, and knockout mice studies have added further weight to the role this receptor plays in mediating the efferent auditory response. Alternate and complementary mechanisms of outer hair cell efferent activity might also be mediated through the nAChR alpha9alpha10, either through secondary calcium stores, second messengers, or direct protein-protein interactions. We investigated protein-protein interactions using a yeast-two-hybrid screen of the nAChR alpha10 intracellular loop against a rat cochlear cDNA library. Among the identified proteins was prosaposin, a precursor of saposins, which have been shown to act as neurotrophic factors in culture, can bind to a putative G0-coupled cell surface receptor, and may be involved in the prevention of cell death. This study and review suggest that nAChR alpha9alpha10 may represent a potential therapeutic target for a variety of ear disorders, including preventing or treating noise-induced hearing loss, or such debilitating disorders as vertigo or tinnitus. Copyright 2006 Wiley-Liss, Inc.
Publication Types:
Review
PMID: 16550589 [PubMed - indexed for MEDLINE]
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2: Eur J Biochem. 2004 Jun;271(12):2305-19.
Alpha-conotoxins as tools for the elucidation of structure and function of neuronal nicotinic acetylcholine receptor subtypes.
Nicke A, Wonnacott S, Lewis RJ.
Max Planck-Institute for Brain Research, Frankfurt, Germany. nicke@mpih-frankfurt.mpg.de
Cone snails comprise approximately 500 species of venomous molluscs, which have evolved the ability to generate multiple toxins with varied and often exquisite selectivity. One class, the alpha-conotoxins, is proving to be a powerful tool for the differentiation of nicotinic acetylcholine receptors (nAChRs). These comprise a large family of complex subtypes, whose significance in physiological functions and pathological conditions is increasingly becoming apparent. After a short introduction into the structure and diversity of nAChRs, this overview summarizes the identification and characterization of alpha-conotoxins with selectivity for neuronal nAChR subtypes and provides examples of their use in defining the compositions and function of neuronal nAChR subtypes in native vertebrate tissues.
Publication Types:
Review
PMID: 15182346 [PubMed - indexed for MEDLINE]
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3: Tanpakushitsu Kakusan Koso. 2004 Jan;49(1):1-10.
[The structure and function of nicotinic acetylcholine receptor]
[Article in Japanese]
Miyazawa A, Fujiyoshi Y.
atsuo@spring8.or.jp
Publication Types:
Review
PMID: 14748133 [PubMed - indexed for MEDLINE]
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4: FEBS Lett. 2003 Nov 27;555(1):91-5.
Structure and action of the nicotinic acetylcholine receptor explored by electron microscopy.
Unwin N.
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. mas@mrc-lmb.cam.ac.uk
The nicotinic acetylcholine (ACh) receptor is the transmitter-gated ion channel at the nerve/muscle synapse. Electron microscopical experiments on isolated postsynaptic membranes have determined the structure of this channel and how the structure changes upon activation. When ACh enters the ligand-binding domain it initiates rotations of the protein chains on opposite sides of the entrance to the membrane-spanning pore. These rotations are communicated to the pore-lining alpha-helices and open the gate--a constricting hydrophobic girdle at the middle of the membrane--by breaking it apart. The movements are small and involve energetically favourable displacements parallel to the membrane plane.
Publication Types:
In Vitro
Review
PMID: 14630325 [PubMed - indexed for MEDLINE]
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5: Ann N Y Acad Sci. 2003 Sep;998:81-92.
Structure and function of AChBP, homologue of the ligand-binding domain of the nicotinic acetylcholine receptor.
Smit AB, Brejc K, Syed N, Sixma TK.
Department of Molecular and Cellular Neurobiology, Faculty of Biology, Research Institute Neurosciences Vrije Universiteit, Amsterdam, The Netherlands. absmit@bio.vu.nl
Acetylcholine-binding protein (AChBP) is a novel protein with high similarity to the extracellular domain of the nicotinic acetylcholine receptor. AChBP lacks the transmembrane domains and intracellular loops typical for the nAChRs. AChBP is secreted from glia cells in the central nervous system of the freshwater snail, Lymnaea stagnalis, where it modulates synaptic transmission. AChBP forms homopentamers with pharmacology that resembles the alpha(7)-type of nicotinic receptors. As such, AChBP is a good model for the ligand-binding domain of the nAChRs. In the crystal structure of AChBP at 2.7 A, each protomer has a modified immunoglobulin fold. Almost all residues previously shown to be involved in ligand binding in the nicotinic receptor are found in a pocket at the subunit interface, which is lined with aromatic residues. The AChBP crystal structure explains many of the biochemical studies on the nicotinic acetylcholine receptors. Surprisingly, the interface between protomers is relatively weakly conserved between families in the superfamily of pentameric ligand-gated ion channels. The lack of conservation has implications for the mechanism of gating of the ion channels.
Publication Types:
In Vitro
Review
PMID: 14592865 [PubMed - indexed for MEDLINE]
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6: Biochim Biophys Acta. 2002 Oct 11;1565(2):287-93.
The structure of the M2 channel-lining segment from the nicotinic acetylcholine receptor.
Montal M, Opella SJ.
Section of Neurobiology, Division of Biology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0366, USA. mmontal@ucsd.edu
The structures of functional peptides corresponding to the predicted channel-lining M2 segment of the nicotinic acetylcholine (AChR) were determined using solution NMR experiments on micelle samples, and solid-state NMR experiments on bilayer samples. The AChR M2 peptide forms a straight transmembrane alpha-helix, with no kinks. M2 inserts in the lipid bilayer at an angle of 12 degrees relative to the bilayer normal, with a rotation about the helix long axis such that the polar residues face the N-terminus of the peptide, which is assigned to be intracellular. A molecular model of the AChR channel pore, constructed from the solid-state NMR 3-D structure of the AChR M2 helix in the membrane assuming a pentameric organization, results in a funnel-like architecture for the channel with the wide opening on the N-terminal intracellular side. A central narrow pore has a diameter ranging from about 3.0 A at its narrowest, to 8.6 A at its widest. Nonpolar residues are predominantly on the exterior of the bundle, while polar residues line the pore. This arrangement is in fair agreement with evidence collected from permeation, mutagenesis, affinity labeling and cysteine accessibility measurements. A pentameric M2 helical bundle may, therefore, represent the structural blueprint for the inner bundle that lines the channel of the nicotinic AChR.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 12409201 [PubMed - indexed for MEDLINE]
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7: Novartis Found Symp. 2002;245:22-9; discussion 29-32, 165-8.
The 2.7 A structure of AChBP, homologue of the ligand-binding domain of the nicotinic acetylcholine receptor.
Brejc K, van Dijk WJ, Smit AB, Sixma TK.
Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam.
Acetylcholine binding protein (AChBP) is a novel protein with high similarity to the extracellular domain of the nicotinic acetylcholine receptor. It is secreted from glia cells in the freshwater snail, Lymnaea stagnalis, where it modulates neuronal transmission. AChBP forms homopentamers with pharmacology that resembles the alpha7 nicotinic receptors. In the crystal structure of AChBP at 2.7 A, each protomer has a modified immunoglobulin fold. Almost all residues shown to be involved in ligand binding in the nicotinic receptor are found in a pocket at the subunit interface. This pocket is lined with aromatic residues, and filled with a HEPES buffer molecule. The AChBP crystal structure explains many of the biochemical studies on the nicotinic acetylcholine receptors. Surprisingly the interface between protomers is relatively weakly conserved between family members in the superfamily of pentameric ligand-gated ion channels. The lack of conservation has implications for the mechanism of gating of the ion channels.
Publication Types:
Review
PMID: 12027010 [PubMed - indexed for MEDLINE]
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8: Curr Med Chem. 2002 Jan;9(1):1-29.
Ligands of neuronal nicotinic acetylcholine receptor (nAChR): inferences from the Hansch and 3-D quantitative structure-activity relationship (QSAR) Models.
Nicolotti O, Pellegrini-Calace M, Altomar C, Carotti A, Carrieri A, Sanz F.
Dipartimento Farmacochimico, Università di Bari, Via Orabona, 4, 70125-Bari, Italy.
Neuronal acetylcholine ion channel receptors (nAChRs), that exist in several subtypes resulting from a different organisation of various subunits around the central ion channel, are involved in a variety of functions and disorders of the central nervous system. There is evidence to implicate a deficit of nAChRs in the symptomatology of severe neurologic pathologies, such as Alzheimer s and Parkinson s diseases. Reliable three-dimensional structures of nAChRs are not available yet, and this hampers adopting structure-based approaches in designing new ligands. Also pharmacophore models are not reliable enough to be used in ligand-based approaches to drug design and little structure-activity work has been reported so far. This paper deals with structure-activity relationships of a wide series of nicotinic ligands. It provides results from a study of the quantitative structure activity relationships (QSARs) based on literature data of about 270 nicotinic agonists, belonging to various chemical classes. The QSAR study was carried out by using either a classical Hansch approach or a Comparative Molecular Field Analysis (CoMFA). Within each congeneric series, Hansch-type equations revealed detrimental steric effects as the factors mainly modulating the receptor affinity, whereas CoMFA allowed us to merge progressively models obtained for each class of congeners into a more general one that showed good cross-validation statistics. The CoMFA coefficient isocontour maps illustrated, at the 3-D level, the most relevant interactions responsible for a high receptor affinity, whereas the robustness of the global three-dimensional QSAR/CoMFA (n = 206, q(2) = 0.749, r(2) = 0.847, s= 0.600) model was supported by the high value of the prediction statistics (r(2)pred = 0.961) and confirmed by the satisfactory predictions of the affinity data of an external set of 18 recently published ligands with chemical structures even quite diverse from those included in the training set.
Publication Types:
Review
PMID: 11864064 [PubMed - indexed for MEDLINE]
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9: Pflugers Arch. 2000;440(5 Suppl):R115-7.
Subunit interface selective toxins as probes of nicotinic acetylcholine receptor structure.
Taylor P, Malanz S, Molles BE, Osaka H, Tsigelny I.
Department of Pharmacology, University of California, San Diego, La Jolla 92093, USA.
The pentametric assembly of the nicotinic acetylcholine receptor with two of the five subunit interfaces serving as a ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits, and their ligand specificity characteristics. The receptor from mammalian muscle, with its circular order of homologous subunits (alphagamma alphadelta beta), assembles in a unique arrangement. The residues governing assembly can be ascertained through mutagenesis. Selectivity of certain natural toxins is sufficient to distinguish between sites at the alphagamma and alphadelta subunit interfaces. By interchanging residues on the gamma and delta subunits through mutagenesis, and ascertaining how they interact with the alpha subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins show a 10,000-fold preference for the alphadelta over alphagamma subunit interface with alphaepsilon falling in between. The waglerins show a 2,000-fold preference for alphaepsilon over the alphagamma and alphadelta interfaces. Finally, the alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alphagamma and alphadelta interfaces over alphaepsilon. Identification of interactive residues through mutagenesis, when coupled with homology modeling of domains and site-directed residue modification, has revealed important elements of receptor structure.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 11005635 [PubMed - indexed for MEDLINE]
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10: J Physiol Paris. 1998 Apr;92(2):79-83.
Toxins selective for subunit interfaces as probes of nicotinic acetylcholine receptor structure.
Taylor P, Osaka H, Molles BE, Sugiyama N, Marchot P, Ackermann EJ, Malany S, McArdle JJ, Sine SM, Tsigelny I.
Department of Pharmacology, University of California, San Diego, La Jolla 92093, USA.
The pentameric structure of the nicotinic acetylcholine receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The receptor, with its circular order of homologous subunits (alpha gamma alpha delta beta), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the alpha gamma and alpha delta interfaces. By interchanging residues on the gamma and delta subunits, and ascertaining how they interact with the alpha-subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins, which contain two disulfide loops and 12-14 amino acids, show a 10,000-fold preference for the alpha delta over the alpha gamma subunit interface with alpha epsilon falling between the two. The waglerins, as 22-24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for alpha epsilon over the alpha gamma and alpha delta interfaces. Finally, the 6700 Da short alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alpha gamma and alpha delta interfaces over alpha epsilon. Selective mutagenesis enables one to also distinguish alpha-neurotoxin binding at the alpha gamma and alpha delta subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of receptor structure and conformation.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9782448 [PubMed - indexed for MEDLINE]
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11: Immunol Rev. 1998 Jun;163:89-120.
Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor.
Tzartos SJ, Barkas T, Cung MT, Mamalaki A, Marraud M, Orlewski P, Papanastasiou D, Sakarellos C, Sakarellos-Daitsiotis M, Tsantili P, Tsikaris V.
Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece. stzartos@compulink.gr
The neuromuscular junction nicotinic acetylcholine receptor (AChR), a pentameric membrane glycoprotein, is the autoantigen involved in the autoimmune disease myasthenia gravis (MG). In animals immunized with intact AChR and in human MG, the anti-AChR antibody response is polyclonal. However, a small extracellular region of the AChR alpha-subunit, the main immunogenic region (MIR), seems to be a major target for anti-AChR antibodies. A major loop containing overlapping epitopes for several anti-MIR monoclonal antibodies (mAbs) lies within residues alpha 67-76 at the extreme synaptic end of each alpha-subunit: however, anti-MIR mAbs are functionally and structurally quite heterogeneous. Anti-MIR mAbs do not affect channel gating, but are very effective in the passive transfer of MG to animals; in contrast, their Fab or Fv fragments protect the AChR from the pathogenic effects of the intact antibodies. Antibodies against the cytoplasmic region of the AChR can be elicited by immunization with denatured AChR and the precise epitopes of many such mAbs have been identified; however, it is unlikely that such antibodies are present in significant amounts in human MG. Antibodies to other extracellular epitopes on all AChR subunits are present in both experimental and human MG; these include antibodies to the acetylcholine-binding site which affect AChR function in various ways and also induce acute experimental MG. Finally, anti-AChR antibodies cross-reactive with non-AChR antigens exist, suggesting that MG may result from molecular mimicry. Despite extensive studies, many gaps remain in our understanding of the antigenic structure of the AChR; especially in relation to human MG. A thorough understanding of the antigenic structure of the AChR is required for an in-depth understanding, and for possible specific immunotherapy, of MG.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9700504 [PubMed - indexed for MEDLINE]
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12: Eur J Biochem. 1996 Aug 1;239(3):539-57.
The emerging three-dimensional structure of a receptor. The nicotinic acetylcholine receptor.
Hucho F, Tsetlin VI, Machold J.
Freic Universität Berlin, Institut für Biochemie, Germany.
The nicotinic acetylcholine receptor is the neurotransmitter receptor with the most-characterized protein structure. The amino acid sequences of its five subunits have been elucidated by cDNA cloning and sequencing. Its shape and dimensions (approximately 12.5 nm x 8 nm) were deduced from electron-microscopy studies. Its subunits are arranged around a five-fold axis of pseudosymmetry in the order (clockwise) alpha H gamma alpha L delta beta. Its two agonist/competitive-antagonist-binding sites have been localized by photolabelling studies to a deep gorge between the subunits near the membrane surface. Its ion channel is formed by five membrane-spanning (M2) helices that are contributed by the five subunits. This finding has been generalized as the Helix M2 model for the superfamily of ligand-gated ion channels. The binding site for regulatory non-competitive antagonists has been localized by photolabelling and site-directed-mutagenesis studies within this ion channel. Therefore a three-dimensional image of the nicotinic acetylcholine receptor is emerging, the most prominent feature of which is an active site that combines the agonist/ competitive-antagonist-binding sites, the regulatory site and the ion channel within a relatively narrow space close to and within the bilayer membrane.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 8774696 [PubMed - indexed for MEDLINE]
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13: Ann Med Interne (Paris). 1996;147(6):442-6.
Antigenic structure of the muscle nicotinic acetylcholine receptor.
Tzartos SJ, Cung MT, Mamalaki A, Marraud M, Papanastasiou D, Sakarellos C, Sakarellos-Daitsiotis M, Tsantili P.
Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9092347 [PubMed - indexed for MEDLINE]
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14: Annu Rev Biophys Biomol Struct. 1996;25:197-229.
Antibodies as tools to study the structure of membrane proteins: the case of the nicotinic acetylcholine receptor.
Conti-Fine BM, Lei S, Mclane KE.
Department of Biochemistry, University of Minnesota, St. Paul 55108, USA.
The nicotinic acetylcholine receptor is the prototype of the ionotropic receptor superfamily of proteins, which includes the closely related gamma- aminobutyric acid type A and glycine receptors, and more distantly related serotonin type-3 and glutamate receptors. Several models of the transmembrane topology of the nicotinic acetylcholine receptor subunits were originally proposed based on hydropathy analysis of their deduced amino acid sequences. Antibodies specific to different epitopes of the nicotinic acetylcholine receptor have proven to be valuable probes for examining the validity of those models. Despite important caveats, a viable model for the transmembrane structure and functional topology of the nicotinic acetylcholine receptor subunits has been obtained from the antibody mapping studies. This model, and the associated methodological shortcomings and obstacles that were overcome in the process of its formulation, can legitimately be extended to other members of the ionotropic receptor superfamily and to other membrane proteins as well.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 8800469 [PubMed - indexed for MEDLINE]
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15: Trends Biochem Sci. 1994 Sep;19(9):383-7.
Beta-structure in the membrane-spanning part of the nicotinic acetylcholine receptor (or how helical are transmembrane helices?).
Hucho F, Görne-Tschelnokow U, Strecker A.
Freie Universität Berlin, Institut für Biochemie, Germany.
The 'four-transmembrane-helix receptors' transmit their signals from the extracellular space to the cytoplasm via an intramembrane domain. In the case of the nicotinic acetylcholine receptor this domain comprises an ion channel formed by homologous secondary structure elements in the receptor subunits. It was believed to be exclusively alpha-helical, but recent experimental evidence questions the widely accepted model: beta-strands seem to be part of the membrane-spanning domain.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 7527165 [PubMed - indexed for MEDLINE]
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16: Crit Rev Biochem Mol Biol. 1994;29(2):69-123.
The nicotinic acetylcholine receptor: structure and autoimmune pathology.
Conti-Tronconi BM, McLane KE, Raftery MA, Grando SA, Protti MP.
Department of Biochemistry, College of Biological Sciences, University of Minnesota, St. Paul 55108.
The nicotinic acetylcholine receptors (AChR) are presently the best-characterized neurotransmitter receptors. They are pentamers of homologous or identical subunits, symmetrically arranged to form a transmembrane cation channel. The AChR subunits form a family of homologous proteins, derived from a common ancestor. An autoimmune response to muscle AChR causes the disease myasthenia gravis. This review summarizes recent developments in the understanding of the AChR structure and its molecular recognition by the immune system in myasthenia.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 8026215 [PubMed - indexed for MEDLINE]
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17: Adv Neuroimmunol. 1994;4(4):339-54.
Nicotinic acetylcholine receptor: structure, function and main immunogenic region.
Mamalaki A, Tzartos SJ.
Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 7719615 [PubMed - indexed for MEDLINE]
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18: Curr Opin Neurobiol. 1992 Jun;2(3):254-62.
Diversity in primary structure and function of neuronal nicotinic acetylcholine receptor channels.
Role LW.
Department of Cell Biology and Anatomy, Columbia University College of Physicians and Surgeons, New York, New York 10032.
Neuronal nicotinic acetylcholine receptors are oligomeric protein complexes whose component subunits are each encoded by a family of homologous genes. The current challenge is to determine the functional contributions of the related subunits to the receptor-linked ion channels they compose and to uncover the physiological impact of the distinct channel classes expressed in vivo. In the past year, new approaches to the analysis of these receptors have yielded important insights into their stoichiometry, pharmacology and functional properties.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 1643408 [PubMed - indexed for MEDLINE]
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19: Adv Exp Med Biol. 1991;287:255-78.
The nicotinic acetylcholine receptor gene family: structure of nicotinic receptors from muscle and neurons and neuronal alpha-bungarotoxin-binding proteins.
Lindstrom J, Schoepfer R, Conroy W, Whiting P, Das M, Saedi M, Anand R.
Salk Institute for Biological Studies, San Diego, CA 92138.
Publication Types:
Review
PMID: 1759611 [PubMed - indexed for MEDLINE]
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20: Braz J Med Biol Res. 1988;21(6):1173-96.
Structure-activity relationship of reversible cholinesterase inhibitors: activation, channel blockade and stereospecificity of the nicotinic acetylcholine receptor-ion channel complex.
Albuquerque EX, Aracava Y, Cintra WM, Brossi A, Schönenberger B, Deshpande SS.
Laboratório de Farmacologia Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brasil.
1. We have shown that all cholinesterase (ChE) inhibitors, in addition to their well-known anti-ChE activity, have multiple effects on the nicotinic acetylcholine receptor-ion channel (AChR) macromolecule resulting from interactions with the agonist recognition site and with sites located at the ion channel component. Activation, competitive antagonism and different types of noncompetitive blockade occurring at similar concentration ranges and contributing in different proportions result in complex and somewhat unpredictable alterations in AChR function. The question is now raised as to how each effect of these compounds contributes to their antidotal property against organophosphorus (OP) poisoning, and what set of actions makes one reversible ChE inhibitor a better antidote. Many lines of evidence support the importance of direct interactions with various sites on the AChR: 1) morphological and toxicological studies with (+) physostigmine showed that anti-ChE activity is not essential to protect animals against toxicity by irreversible ChE inhibitors; 2) (-)physostigmine is far more effective against OP poisoning; 3) open channel blockers such as mecamylamine with no significant anti-ChE activity enhance the protective action of (-)physostigmine; 4) neostigmine, pyridostigmine, (-)physostigmine and (+)physostigmine showed qualitatively and quantitatively distinct toxicity and damage to endplate morphology and function. 2. In prophylaxis and during the very early phase of OP poisoning, carbamates, especially (-)physostigmine combined with mecamylamine and atropine, could protect almost 100% of the animals exposed to multiple lethal doses of OPs. Electrophysiological data showed that (-)physostigmine, among several reversible ChE inhibitors, showed greater potency in depressing both endplate current (EPC) peak amplitude and tau EPC. Therefore, concerning neuromuscular transmission, it seems that the higher the potency of a drug in reducing endplate permeability, the better is its protection against OP toxicity. A reversible open channel blockade combined with some agonist property helps to decrease the effect of ACh at its agonist site and to reduce the ion permeability of open channels. It should be pointed out that, during the later phase of OP poisoning, AChR desensitization should be most prevalent. Thus, a drug that can remove the AChR from this rather irreversible state to a more reversible blocked state should be a better protector. Indeed, oximes such as 2-PAM and a more potent analog, HI-6, produce multiple alterations in AChR function that comprise increased channel activation and open-channel blockade.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication Types:
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 3074841 [PubMed - indexed for MEDLINE]
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21: Seikagaku. 1986 Oct;58(10):1275-91.
[Structure and function of the nicotinic acetylcholine receptor]
[Article in Japanese]
Mishina M.
Publication Types:
Review
PMID: 2434583 [PubMed - indexed for MEDLINE]
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22: Physiol Rev. 1984 Oct;64(4):1162-239.
Nicotinic receptor of acetylcholine: structure of an oligomeric integral membrane protein.
Popot JL, Changeux JP.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 6208568 [PubMed - indexed for MEDLINE]
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23: Annu Rev Biochem. 1982;51:491-530.
The nicotinic cholinergic receptor: correlation of molecular structure with functional properties.
Conti-Tronconi BM, Raftery MA.
Publication Types:
Review
PMID: 7051962 [PubMed - indexed for MEDLINE]
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24: Prog Clin Biol Res. 1982;79:73-85.
The structure of the nicotinic acetylcholine receptor.
Hamilton SL.
The nicotinic acetylcholine receptor of the electric ray is currently one of the most extensively studied integral membrane proteins. A very speculative model for the structure of acetylcholine receptor in the membrane is shown in Fig. 1. This model does not take into account the extremely high density of receptor in the subsynaptic region of the membrane. The receptor is an oligomeric glycoprotein composed of five subunits, all of which are exposed externally, span the lipid bilayer, and are exposed cytoplasmically. Although the subunits have considerable sequence homology, they arise from the translation of different messenger RNAs. The naturally occurring form of the Torpedo receptor is a dimer, but monomer is also functionally active. Each receptor monomer has two binding sites for agonists and competitive antagonists but probably only one site for specific binding of local anesthetics. This latter site appears to be in the open ion channel near the center of the membrane.
Publication Types:
Review
PMID: 7045887 [PubMed - indexed for MEDLINE]
Nicotinic acetylcholine receptor structure and function in the efferent auditory system.
Lustig LR.
Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, California 941430, USA. llustig@ohns.ucsf.edu
This article reviews and presents new data regarding the nicotinic acetylcholine receptor subunits alpha9 and alpha10. Although phylogentically ancient, these subunits have only recently been identified as critical components of the efferent auditory system and medial olivocochlear pathway. This pathway is important in auditory processing by modulating outer hair cell function to broadly tune the cochlea and improve signal detection in noise. Pharmacologic properties of the functionally expressed alpha9alpha10 receptor closely resemble the cholinergic response of outer hair cells. Molecular, immunohistochemical, and knockout mice studies have added further weight to the role this receptor plays in mediating the efferent auditory response. Alternate and complementary mechanisms of outer hair cell efferent activity might also be mediated through the nAChR alpha9alpha10, either through secondary calcium stores, second messengers, or direct protein-protein interactions. We investigated protein-protein interactions using a yeast-two-hybrid screen of the nAChR alpha10 intracellular loop against a rat cochlear cDNA library. Among the identified proteins was prosaposin, a precursor of saposins, which have been shown to act as neurotrophic factors in culture, can bind to a putative G0-coupled cell surface receptor, and may be involved in the prevention of cell death. This study and review suggest that nAChR alpha9alpha10 may represent a potential therapeutic target for a variety of ear disorders, including preventing or treating noise-induced hearing loss, or such debilitating disorders as vertigo or tinnitus. Copyright 2006 Wiley-Liss, Inc.
Publication Types:
Review
PMID: 16550589 [PubMed - indexed for MEDLINE]
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2: Eur J Biochem. 2004 Jun;271(12):2305-19.
Alpha-conotoxins as tools for the elucidation of structure and function of neuronal nicotinic acetylcholine receptor subtypes.
Nicke A, Wonnacott S, Lewis RJ.
Max Planck-Institute for Brain Research, Frankfurt, Germany. nicke@mpih-frankfurt.mpg.de
Cone snails comprise approximately 500 species of venomous molluscs, which have evolved the ability to generate multiple toxins with varied and often exquisite selectivity. One class, the alpha-conotoxins, is proving to be a powerful tool for the differentiation of nicotinic acetylcholine receptors (nAChRs). These comprise a large family of complex subtypes, whose significance in physiological functions and pathological conditions is increasingly becoming apparent. After a short introduction into the structure and diversity of nAChRs, this overview summarizes the identification and characterization of alpha-conotoxins with selectivity for neuronal nAChR subtypes and provides examples of their use in defining the compositions and function of neuronal nAChR subtypes in native vertebrate tissues.
Publication Types:
Review
PMID: 15182346 [PubMed - indexed for MEDLINE]
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3: Tanpakushitsu Kakusan Koso. 2004 Jan;49(1):1-10.
[The structure and function of nicotinic acetylcholine receptor]
[Article in Japanese]
Miyazawa A, Fujiyoshi Y.
atsuo@spring8.or.jp
Publication Types:
Review
PMID: 14748133 [PubMed - indexed for MEDLINE]
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4: FEBS Lett. 2003 Nov 27;555(1):91-5.
Structure and action of the nicotinic acetylcholine receptor explored by electron microscopy.
Unwin N.
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. mas@mrc-lmb.cam.ac.uk
The nicotinic acetylcholine (ACh) receptor is the transmitter-gated ion channel at the nerve/muscle synapse. Electron microscopical experiments on isolated postsynaptic membranes have determined the structure of this channel and how the structure changes upon activation. When ACh enters the ligand-binding domain it initiates rotations of the protein chains on opposite sides of the entrance to the membrane-spanning pore. These rotations are communicated to the pore-lining alpha-helices and open the gate--a constricting hydrophobic girdle at the middle of the membrane--by breaking it apart. The movements are small and involve energetically favourable displacements parallel to the membrane plane.
Publication Types:
In Vitro
Review
PMID: 14630325 [PubMed - indexed for MEDLINE]
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5: Ann N Y Acad Sci. 2003 Sep;998:81-92.
Structure and function of AChBP, homologue of the ligand-binding domain of the nicotinic acetylcholine receptor.
Smit AB, Brejc K, Syed N, Sixma TK.
Department of Molecular and Cellular Neurobiology, Faculty of Biology, Research Institute Neurosciences Vrije Universiteit, Amsterdam, The Netherlands. absmit@bio.vu.nl
Acetylcholine-binding protein (AChBP) is a novel protein with high similarity to the extracellular domain of the nicotinic acetylcholine receptor. AChBP lacks the transmembrane domains and intracellular loops typical for the nAChRs. AChBP is secreted from glia cells in the central nervous system of the freshwater snail, Lymnaea stagnalis, where it modulates synaptic transmission. AChBP forms homopentamers with pharmacology that resembles the alpha(7)-type of nicotinic receptors. As such, AChBP is a good model for the ligand-binding domain of the nAChRs. In the crystal structure of AChBP at 2.7 A, each protomer has a modified immunoglobulin fold. Almost all residues previously shown to be involved in ligand binding in the nicotinic receptor are found in a pocket at the subunit interface, which is lined with aromatic residues. The AChBP crystal structure explains many of the biochemical studies on the nicotinic acetylcholine receptors. Surprisingly, the interface between protomers is relatively weakly conserved between families in the superfamily of pentameric ligand-gated ion channels. The lack of conservation has implications for the mechanism of gating of the ion channels.
Publication Types:
In Vitro
Review
PMID: 14592865 [PubMed - indexed for MEDLINE]
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6: Biochim Biophys Acta. 2002 Oct 11;1565(2):287-93.
The structure of the M2 channel-lining segment from the nicotinic acetylcholine receptor.
Montal M, Opella SJ.
Section of Neurobiology, Division of Biology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0366, USA. mmontal@ucsd.edu
The structures of functional peptides corresponding to the predicted channel-lining M2 segment of the nicotinic acetylcholine (AChR) were determined using solution NMR experiments on micelle samples, and solid-state NMR experiments on bilayer samples. The AChR M2 peptide forms a straight transmembrane alpha-helix, with no kinks. M2 inserts in the lipid bilayer at an angle of 12 degrees relative to the bilayer normal, with a rotation about the helix long axis such that the polar residues face the N-terminus of the peptide, which is assigned to be intracellular. A molecular model of the AChR channel pore, constructed from the solid-state NMR 3-D structure of the AChR M2 helix in the membrane assuming a pentameric organization, results in a funnel-like architecture for the channel with the wide opening on the N-terminal intracellular side. A central narrow pore has a diameter ranging from about 3.0 A at its narrowest, to 8.6 A at its widest. Nonpolar residues are predominantly on the exterior of the bundle, while polar residues line the pore. This arrangement is in fair agreement with evidence collected from permeation, mutagenesis, affinity labeling and cysteine accessibility measurements. A pentameric M2 helical bundle may, therefore, represent the structural blueprint for the inner bundle that lines the channel of the nicotinic AChR.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 12409201 [PubMed - indexed for MEDLINE]
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7: Novartis Found Symp. 2002;245:22-9; discussion 29-32, 165-8.
The 2.7 A structure of AChBP, homologue of the ligand-binding domain of the nicotinic acetylcholine receptor.
Brejc K, van Dijk WJ, Smit AB, Sixma TK.
Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam.
Acetylcholine binding protein (AChBP) is a novel protein with high similarity to the extracellular domain of the nicotinic acetylcholine receptor. It is secreted from glia cells in the freshwater snail, Lymnaea stagnalis, where it modulates neuronal transmission. AChBP forms homopentamers with pharmacology that resembles the alpha7 nicotinic receptors. In the crystal structure of AChBP at 2.7 A, each protomer has a modified immunoglobulin fold. Almost all residues shown to be involved in ligand binding in the nicotinic receptor are found in a pocket at the subunit interface. This pocket is lined with aromatic residues, and filled with a HEPES buffer molecule. The AChBP crystal structure explains many of the biochemical studies on the nicotinic acetylcholine receptors. Surprisingly the interface between protomers is relatively weakly conserved between family members in the superfamily of pentameric ligand-gated ion channels. The lack of conservation has implications for the mechanism of gating of the ion channels.
Publication Types:
Review
PMID: 12027010 [PubMed - indexed for MEDLINE]
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8: Curr Med Chem. 2002 Jan;9(1):1-29.
Ligands of neuronal nicotinic acetylcholine receptor (nAChR): inferences from the Hansch and 3-D quantitative structure-activity relationship (QSAR) Models.
Nicolotti O, Pellegrini-Calace M, Altomar C, Carotti A, Carrieri A, Sanz F.
Dipartimento Farmacochimico, Università di Bari, Via Orabona, 4, 70125-Bari, Italy.
Neuronal acetylcholine ion channel receptors (nAChRs), that exist in several subtypes resulting from a different organisation of various subunits around the central ion channel, are involved in a variety of functions and disorders of the central nervous system. There is evidence to implicate a deficit of nAChRs in the symptomatology of severe neurologic pathologies, such as Alzheimer s and Parkinson s diseases. Reliable three-dimensional structures of nAChRs are not available yet, and this hampers adopting structure-based approaches in designing new ligands. Also pharmacophore models are not reliable enough to be used in ligand-based approaches to drug design and little structure-activity work has been reported so far. This paper deals with structure-activity relationships of a wide series of nicotinic ligands. It provides results from a study of the quantitative structure activity relationships (QSARs) based on literature data of about 270 nicotinic agonists, belonging to various chemical classes. The QSAR study was carried out by using either a classical Hansch approach or a Comparative Molecular Field Analysis (CoMFA). Within each congeneric series, Hansch-type equations revealed detrimental steric effects as the factors mainly modulating the receptor affinity, whereas CoMFA allowed us to merge progressively models obtained for each class of congeners into a more general one that showed good cross-validation statistics. The CoMFA coefficient isocontour maps illustrated, at the 3-D level, the most relevant interactions responsible for a high receptor affinity, whereas the robustness of the global three-dimensional QSAR/CoMFA (n = 206, q(2) = 0.749, r(2) = 0.847, s= 0.600) model was supported by the high value of the prediction statistics (r(2)pred = 0.961) and confirmed by the satisfactory predictions of the affinity data of an external set of 18 recently published ligands with chemical structures even quite diverse from those included in the training set.
Publication Types:
Review
PMID: 11864064 [PubMed - indexed for MEDLINE]
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9: Pflugers Arch. 2000;440(5 Suppl):R115-7.
Subunit interface selective toxins as probes of nicotinic acetylcholine receptor structure.
Taylor P, Malanz S, Molles BE, Osaka H, Tsigelny I.
Department of Pharmacology, University of California, San Diego, La Jolla 92093, USA.
The pentametric assembly of the nicotinic acetylcholine receptor with two of the five subunit interfaces serving as a ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits, and their ligand specificity characteristics. The receptor from mammalian muscle, with its circular order of homologous subunits (alphagamma alphadelta beta), assembles in a unique arrangement. The residues governing assembly can be ascertained through mutagenesis. Selectivity of certain natural toxins is sufficient to distinguish between sites at the alphagamma and alphadelta subunit interfaces. By interchanging residues on the gamma and delta subunits through mutagenesis, and ascertaining how they interact with the alpha subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins show a 10,000-fold preference for the alphadelta over alphagamma subunit interface with alphaepsilon falling in between. The waglerins show a 2,000-fold preference for alphaepsilon over the alphagamma and alphadelta interfaces. Finally, the alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alphagamma and alphadelta interfaces over alphaepsilon. Identification of interactive residues through mutagenesis, when coupled with homology modeling of domains and site-directed residue modification, has revealed important elements of receptor structure.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 11005635 [PubMed - indexed for MEDLINE]
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10: J Physiol Paris. 1998 Apr;92(2):79-83.
Toxins selective for subunit interfaces as probes of nicotinic acetylcholine receptor structure.
Taylor P, Osaka H, Molles BE, Sugiyama N, Marchot P, Ackermann EJ, Malany S, McArdle JJ, Sine SM, Tsigelny I.
Department of Pharmacology, University of California, San Diego, La Jolla 92093, USA.
The pentameric structure of the nicotinic acetylcholine receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The receptor, with its circular order of homologous subunits (alpha gamma alpha delta beta), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the alpha gamma and alpha delta interfaces. By interchanging residues on the gamma and delta subunits, and ascertaining how they interact with the alpha-subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins, which contain two disulfide loops and 12-14 amino acids, show a 10,000-fold preference for the alpha delta over the alpha gamma subunit interface with alpha epsilon falling between the two. The waglerins, as 22-24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for alpha epsilon over the alpha gamma and alpha delta interfaces. Finally, the 6700 Da short alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alpha gamma and alpha delta interfaces over alpha epsilon. Selective mutagenesis enables one to also distinguish alpha-neurotoxin binding at the alpha gamma and alpha delta subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of receptor structure and conformation.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9782448 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: Immunol Rev. 1998 Jun;163:89-120.
Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor.
Tzartos SJ, Barkas T, Cung MT, Mamalaki A, Marraud M, Orlewski P, Papanastasiou D, Sakarellos C, Sakarellos-Daitsiotis M, Tsantili P, Tsikaris V.
Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece. stzartos@compulink.gr
The neuromuscular junction nicotinic acetylcholine receptor (AChR), a pentameric membrane glycoprotein, is the autoantigen involved in the autoimmune disease myasthenia gravis (MG). In animals immunized with intact AChR and in human MG, the anti-AChR antibody response is polyclonal. However, a small extracellular region of the AChR alpha-subunit, the main immunogenic region (MIR), seems to be a major target for anti-AChR antibodies. A major loop containing overlapping epitopes for several anti-MIR monoclonal antibodies (mAbs) lies within residues alpha 67-76 at the extreme synaptic end of each alpha-subunit: however, anti-MIR mAbs are functionally and structurally quite heterogeneous. Anti-MIR mAbs do not affect channel gating, but are very effective in the passive transfer of MG to animals; in contrast, their Fab or Fv fragments protect the AChR from the pathogenic effects of the intact antibodies. Antibodies against the cytoplasmic region of the AChR can be elicited by immunization with denatured AChR and the precise epitopes of many such mAbs have been identified; however, it is unlikely that such antibodies are present in significant amounts in human MG. Antibodies to other extracellular epitopes on all AChR subunits are present in both experimental and human MG; these include antibodies to the acetylcholine-binding site which affect AChR function in various ways and also induce acute experimental MG. Finally, anti-AChR antibodies cross-reactive with non-AChR antigens exist, suggesting that MG may result from molecular mimicry. Despite extensive studies, many gaps remain in our understanding of the antigenic structure of the AChR; especially in relation to human MG. A thorough understanding of the antigenic structure of the AChR is required for an in-depth understanding, and for possible specific immunotherapy, of MG.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9700504 [PubMed - indexed for MEDLINE]
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12: Eur J Biochem. 1996 Aug 1;239(3):539-57.
The emerging three-dimensional structure of a receptor. The nicotinic acetylcholine receptor.
Hucho F, Tsetlin VI, Machold J.
Freic Universität Berlin, Institut für Biochemie, Germany.
The nicotinic acetylcholine receptor is the neurotransmitter receptor with the most-characterized protein structure. The amino acid sequences of its five subunits have been elucidated by cDNA cloning and sequencing. Its shape and dimensions (approximately 12.5 nm x 8 nm) were deduced from electron-microscopy studies. Its subunits are arranged around a five-fold axis of pseudosymmetry in the order (clockwise) alpha H gamma alpha L delta beta. Its two agonist/competitive-antagonist-binding sites have been localized by photolabelling studies to a deep gorge between the subunits near the membrane surface. Its ion channel is formed by five membrane-spanning (M2) helices that are contributed by the five subunits. This finding has been generalized as the Helix M2 model for the superfamily of ligand-gated ion channels. The binding site for regulatory non-competitive antagonists has been localized by photolabelling and site-directed-mutagenesis studies within this ion channel. Therefore a three-dimensional image of the nicotinic acetylcholine receptor is emerging, the most prominent feature of which is an active site that combines the agonist/ competitive-antagonist-binding sites, the regulatory site and the ion channel within a relatively narrow space close to and within the bilayer membrane.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 8774696 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
13: Ann Med Interne (Paris). 1996;147(6):442-6.
Antigenic structure of the muscle nicotinic acetylcholine receptor.
Tzartos SJ, Cung MT, Mamalaki A, Marraud M, Papanastasiou D, Sakarellos C, Sakarellos-Daitsiotis M, Tsantili P.
Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9092347 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
14: Annu Rev Biophys Biomol Struct. 1996;25:197-229.
Antibodies as tools to study the structure of membrane proteins: the case of the nicotinic acetylcholine receptor.
Conti-Fine BM, Lei S, Mclane KE.
Department of Biochemistry, University of Minnesota, St. Paul 55108, USA.
The nicotinic acetylcholine receptor is the prototype of the ionotropic receptor superfamily of proteins, which includes the closely related gamma- aminobutyric acid type A and glycine receptors, and more distantly related serotonin type-3 and glutamate receptors. Several models of the transmembrane topology of the nicotinic acetylcholine receptor subunits were originally proposed based on hydropathy analysis of their deduced amino acid sequences. Antibodies specific to different epitopes of the nicotinic acetylcholine receptor have proven to be valuable probes for examining the validity of those models. Despite important caveats, a viable model for the transmembrane structure and functional topology of the nicotinic acetylcholine receptor subunits has been obtained from the antibody mapping studies. This model, and the associated methodological shortcomings and obstacles that were overcome in the process of its formulation, can legitimately be extended to other members of the ionotropic receptor superfamily and to other membrane proteins as well.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 8800469 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
15: Trends Biochem Sci. 1994 Sep;19(9):383-7.
Beta-structure in the membrane-spanning part of the nicotinic acetylcholine receptor (or how helical are transmembrane helices?).
Hucho F, Görne-Tschelnokow U, Strecker A.
Freie Universität Berlin, Institut für Biochemie, Germany.
The 'four-transmembrane-helix receptors' transmit their signals from the extracellular space to the cytoplasm via an intramembrane domain. In the case of the nicotinic acetylcholine receptor this domain comprises an ion channel formed by homologous secondary structure elements in the receptor subunits. It was believed to be exclusively alpha-helical, but recent experimental evidence questions the widely accepted model: beta-strands seem to be part of the membrane-spanning domain.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 7527165 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
16: Crit Rev Biochem Mol Biol. 1994;29(2):69-123.
The nicotinic acetylcholine receptor: structure and autoimmune pathology.
Conti-Tronconi BM, McLane KE, Raftery MA, Grando SA, Protti MP.
Department of Biochemistry, College of Biological Sciences, University of Minnesota, St. Paul 55108.
The nicotinic acetylcholine receptors (AChR) are presently the best-characterized neurotransmitter receptors. They are pentamers of homologous or identical subunits, symmetrically arranged to form a transmembrane cation channel. The AChR subunits form a family of homologous proteins, derived from a common ancestor. An autoimmune response to muscle AChR causes the disease myasthenia gravis. This review summarizes recent developments in the understanding of the AChR structure and its molecular recognition by the immune system in myasthenia.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 8026215 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
17: Adv Neuroimmunol. 1994;4(4):339-54.
Nicotinic acetylcholine receptor: structure, function and main immunogenic region.
Mamalaki A, Tzartos SJ.
Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 7719615 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
18: Curr Opin Neurobiol. 1992 Jun;2(3):254-62.
Diversity in primary structure and function of neuronal nicotinic acetylcholine receptor channels.
Role LW.
Department of Cell Biology and Anatomy, Columbia University College of Physicians and Surgeons, New York, New York 10032.
Neuronal nicotinic acetylcholine receptors are oligomeric protein complexes whose component subunits are each encoded by a family of homologous genes. The current challenge is to determine the functional contributions of the related subunits to the receptor-linked ion channels they compose and to uncover the physiological impact of the distinct channel classes expressed in vivo. In the past year, new approaches to the analysis of these receptors have yielded important insights into their stoichiometry, pharmacology and functional properties.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 1643408 [PubMed - indexed for MEDLINE]
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19: Adv Exp Med Biol. 1991;287:255-78.
The nicotinic acetylcholine receptor gene family: structure of nicotinic receptors from muscle and neurons and neuronal alpha-bungarotoxin-binding proteins.
Lindstrom J, Schoepfer R, Conroy W, Whiting P, Das M, Saedi M, Anand R.
Salk Institute for Biological Studies, San Diego, CA 92138.
Publication Types:
Review
PMID: 1759611 [PubMed - indexed for MEDLINE]
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20: Braz J Med Biol Res. 1988;21(6):1173-96.
Structure-activity relationship of reversible cholinesterase inhibitors: activation, channel blockade and stereospecificity of the nicotinic acetylcholine receptor-ion channel complex.
Albuquerque EX, Aracava Y, Cintra WM, Brossi A, Schönenberger B, Deshpande SS.
Laboratório de Farmacologia Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brasil.
1. We have shown that all cholinesterase (ChE) inhibitors, in addition to their well-known anti-ChE activity, have multiple effects on the nicotinic acetylcholine receptor-ion channel (AChR) macromolecule resulting from interactions with the agonist recognition site and with sites located at the ion channel component. Activation, competitive antagonism and different types of noncompetitive blockade occurring at similar concentration ranges and contributing in different proportions result in complex and somewhat unpredictable alterations in AChR function. The question is now raised as to how each effect of these compounds contributes to their antidotal property against organophosphorus (OP) poisoning, and what set of actions makes one reversible ChE inhibitor a better antidote. Many lines of evidence support the importance of direct interactions with various sites on the AChR: 1) morphological and toxicological studies with (+) physostigmine showed that anti-ChE activity is not essential to protect animals against toxicity by irreversible ChE inhibitors; 2) (-)physostigmine is far more effective against OP poisoning; 3) open channel blockers such as mecamylamine with no significant anti-ChE activity enhance the protective action of (-)physostigmine; 4) neostigmine, pyridostigmine, (-)physostigmine and (+)physostigmine showed qualitatively and quantitatively distinct toxicity and damage to endplate morphology and function. 2. In prophylaxis and during the very early phase of OP poisoning, carbamates, especially (-)physostigmine combined with mecamylamine and atropine, could protect almost 100% of the animals exposed to multiple lethal doses of OPs. Electrophysiological data showed that (-)physostigmine, among several reversible ChE inhibitors, showed greater potency in depressing both endplate current (EPC) peak amplitude and tau EPC. Therefore, concerning neuromuscular transmission, it seems that the higher the potency of a drug in reducing endplate permeability, the better is its protection against OP toxicity. A reversible open channel blockade combined with some agonist property helps to decrease the effect of ACh at its agonist site and to reduce the ion permeability of open channels. It should be pointed out that, during the later phase of OP poisoning, AChR desensitization should be most prevalent. Thus, a drug that can remove the AChR from this rather irreversible state to a more reversible blocked state should be a better protector. Indeed, oximes such as 2-PAM and a more potent analog, HI-6, produce multiple alterations in AChR function that comprise increased channel activation and open-channel blockade.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication Types:
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 3074841 [PubMed - indexed for MEDLINE]
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21: Seikagaku. 1986 Oct;58(10):1275-91.
[Structure and function of the nicotinic acetylcholine receptor]
[Article in Japanese]
Mishina M.
Publication Types:
Review
PMID: 2434583 [PubMed - indexed for MEDLINE]
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22: Physiol Rev. 1984 Oct;64(4):1162-239.
Nicotinic receptor of acetylcholine: structure of an oligomeric integral membrane protein.
Popot JL, Changeux JP.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 6208568 [PubMed - indexed for MEDLINE]
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23: Annu Rev Biochem. 1982;51:491-530.
The nicotinic cholinergic receptor: correlation of molecular structure with functional properties.
Conti-Tronconi BM, Raftery MA.
Publication Types:
Review
PMID: 7051962 [PubMed - indexed for MEDLINE]
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24: Prog Clin Biol Res. 1982;79:73-85.
The structure of the nicotinic acetylcholine receptor.
Hamilton SL.
The nicotinic acetylcholine receptor of the electric ray is currently one of the most extensively studied integral membrane proteins. A very speculative model for the structure of acetylcholine receptor in the membrane is shown in Fig. 1. This model does not take into account the extremely high density of receptor in the subsynaptic region of the membrane. The receptor is an oligomeric glycoprotein composed of five subunits, all of which are exposed externally, span the lipid bilayer, and are exposed cytoplasmically. Although the subunits have considerable sequence homology, they arise from the translation of different messenger RNAs. The naturally occurring form of the Torpedo receptor is a dimer, but monomer is also functionally active. Each receptor monomer has two binding sites for agonists and competitive antagonists but probably only one site for specific binding of local anesthetics. This latter site appears to be in the open ion channel near the center of the membrane.
Publication Types:
Review
PMID: 7045887 [PubMed - indexed for MEDLINE]
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