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In general, there are no overt signs of intoxication or incapacitation, and the health costs may take years or even decades to manifest. In any case, the changes in nAChR expression and function that occur with chronic nicotine use are believed to produce a dependence, so a smoker attempting to quit manifests a withdrawal syndrome that encourages relapse. The oldest and most basic approach for aiding smoking cessation has been nicotine replacement therapy, substituting nicotine in alternative forms, such as a chewing gum or a patch, for the nicotine delivered by cigarettes.

While these approaches do separate nicotine from other potential carcinogens in smoke, it is questionable whether they address nicotine addiction or merely assuage it with another manner of applying the drug. It can be argued that nicotine patches will not provide the short-term reinforcing effects that would come from the pulsatile delivery of nicotine to the dopamine-releasing centers in the brain. It also likely that the steady delivery of low concentrations of nicotine will sufficiently desensitize brain receptors so that they would respond less effectively to nicotine as delivered by a cigarette.

This less-than-ideal profile encourages the further development of new partial agonists based on either cytisine Mineur et al. It has also been proposed that nAChR antagonists could be used for smoking cessation therapies. For example, the neuronal nicotinic antagonist mecamylamine used in conjunction with transdermal nicotine patches was more effective than patch therapy alone Rose et al.

The atypical antidepressant bupropion is also used for smoking cessation therapy, with an efficacy roughly equivalent to that of varenicline. An isomer of mecamylamine was advanced to Phase III clinical trials for depression Lindsley, but was found to lack efficacy. The balance between cholinergic and dopaminergic activity in the basal ganglia is important for control of motor function.

It seems that the earlier positive results were probably due to the management of hypercholinergic activity that occurred as a side effect of the antipsychotic drugs dopamine-receptor blockers that the patients were taking as their standard therapy. Most drugs that target Cys-loop receptors do so at either the agonist binding sites or the ion channel, but there is growing appreciation nAChR may also be targeted by drugs working at allosteric binding sites.

Benzodiazepines bind to alternative interfaces and can increase the affinity of efficacy of GABA. The kinetic models and energy landscapes described previously can only be effectively applied to heteromeric nAChR that manifest high-affinity desensitized states. Additionally, there are compounds that bind to both the TM PAM site and a novel site in the extracellular domain to produce both transient activation when applied alone and persistent potentiation of subsequent agonist applications Horenstein et al. Subsequent work has identified an interesting range of properties for related compounds, including allosteric antagonism Gill-Thind et al.

Interestingly, NS was shown not to be strictly an antagonist, but rather a very weak partial agonist that produced prolonged desensitization that could be partly reversed by co-application with a Type II PAM Briggs et al. Limited trials are still ongoing with GTS as a treatment for negative and cognitive symptoms of schizophrenia Kem et al.

The best drugs in these areas may not be channel activators, but rather silent agonists like NS Papke et al.

Hallucinogen

Nicotinic acetylcholine receptors stand out from a large family of related proteins as being the essential initiators of every human movement, including the act of speaking. In the brain, they may help in the shaping of the words to be spoken, but in animals, they may be removed genetically from the brain with little apparent effect, except for loss of interest in nicotine.


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For further reading, I recommend this excellent and comprehensive textbook dedicated just to nicotinic receptors:. I also thank Clare Stokes for her careful proofreading and thoughtful comments. Akabas, M. Acetylcholine receptor channel structure probed in cysteine-substitution mutants. Science, , — Find this resource:. Aldrich, R. A reinterpretation of mammalian sodium channel gating based on single channel recording. Nature, , — Alsharari, S. Functional role of alpha7 nicotinic receptor in chronic neuropathic and inflammatory pain: Studies in transgenic mice.

Biochemical Pharmacology, 86 8 , — Andersen, N. Stoichiometry for activation of neuronal alpha7 nicotinic receptors. Assayag, E. Bronchodilatory and anti-inflammatory effects of ASM, a nicotinic receptor ligand, developed for the treatment of asthma. PLoS One, 9 1 , e Azam, L. Expression of neuronal nicotinic acetylcholine receptor subunit mRNAs within midbrain dopamine neurons.

Edited by Arin Bhattacharjee

Journal of Comparative Neurology, 3 , — Ballivet, M. Molecular cloning of cDNA coding for the gamma subunit of Torpedo acetylcholine receptor. Bartol, T. Monte Carlo simulation of miniature endplate current generation in the vertebrate neuromuscular junction. Biophysical Journal, 59 6 , — Becchetti, A. The role of nicotinic acetylcholine receptors in autosomal dominant nocturnal frontal lobe epilepsy. Frontiers in Physiology, 6 , Beers, W.

Structure and activity of acetylcholine. Bertrand, D. Unconventional pharmacology of a neuronal nicotinic receptor mutated in the channel domain. Mutations at two distinct sites within the channel domain M2 alter calcium permeability of neuronal alpha 7 nicotinic receptor.


  1. Nicotinic Acetylcholine Receptors!
  2. Introduction!
  3. International Mathematical Olympiads, 1959-1977.
  4. Introduction to metadata.
  5. Betz, H. Ligand gated channels in the brain: The amino acid receptor superfamily. Neuron, 5 , — Bianchi, M. Neuropharmacology, 41 6 , — Bisson, W. Homology modeling and dynamics of the extracellular domain of rat and human neuronal nicotinic acetylcholine receptor subtypes alpha4beta2 and alpha7.

    Nicotinic Acetylcholine Receptors - Oxford Handbooks

    Journal of Molecular Modeling, 14 10 , — Bocquet, N. X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family. Boess, F. The novel alpha7 nicotinic acetylcholine receptor agonist N-[ 3R azabicyclo[2. Journal of Pharmacology and Experimental Therapeutics, 2 , — Boulter, J. Functional expression of two neural nicotinic acetylcholine receptors from cDNA clones identifies a gene family.

    Bouzat, C. The interface between extracellular and transmembrane domains of homomeric Cys-loop receptors governs open-channel lifetime and rate of desensitization. Journal of Neuroscience, 28 31 , — Coupling of agonist binding to channel gating in an ACh-binding protein linked to an ion channel. Brejc, K. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.

    Briggs, C. Role of channel activation in cognitive enhancement mediated by alpha7 nicotinic acetylcholine receptors. British Journal of Pharmacology, 6 , — Campbell, A. Treatment of severe hypertension with hexamethonium bromide. British Medical Journal, 2 , — Cash, D. Acetylcholine-receptor-mediated ion fluxes in Electrophorus electricus and Torpedo californica membrane vesicles.

    Reviews of Physiology, Biochemistry, and Pharmacology, , 73— Castillo, M. Dual role of the RIC-3 protein in trafficking of serotonin and nicotinic acetylcholine receptors. Journal of Biological Chemistry, 29 , — Champtiaux, N. Knockout and knockin mice to investigate the role of nicotinic receptors in the central nervous system.

    Progress in Brain Research, , — Chen, X. Variants in nicotinic acetylcholine receptors alpha5 and alpha3 increase risks to nicotine dependence. Chesselet, M. Presynaptic regulation of neurotransmitter release in the brain. Neuroscience, 12 , — Chini, B. Neuronal-type alpha-bungarotoxin receptors and the alpha 5-nicotinic receptor subunit gene are expressed in neuronal and nonneuronal human cell lines.

    Clarke, P. Nicotinic binding in rat brain: Autoradiographic comparison of [ 3 H] acetylcholine [ 3 H] nicotine and [ I]-alpha-bungarotoxin. Journal of Neuroscience, 5 , — Coe, J. Varenicline: An alpha4beta2 nicotinic receptor partial agonist for smoking cessation. Journal of Medical Chemistry, 48 10 , — Colquhoun, D. The principles of the stochastic interpretation of ion channel mechanisms. Neher Eds. New York: Plenum Press. Activation of ion channels in the frog end-plate by high concentrations of acetylcholine.

    Journal of Physiology, , — Fast events in single-channel currents activated by acetylcholine and its analogues at the frog muscle end-plate. Corey-Bloom, J. International Journal of Clinical Practice, 57 3 , — Corringer, P. Nicotinic receptors at the amino acid level.

    Annual Review of Pharmacology and Toxicology, 40 , — Dani, J. Ion-channel entrances influence permeation: Net charge size, shape, and binding considerations. Biophysical Journal, 49 , — David, R. Biochemical and functional properties of distinct nicotinic acetylcholine receptors in the superior cervical ganglion of mice with targeted deletions of nAChR subunit genes. European Journal of Neuroscience, 31 6 , — Davies, P. Journal of Biological Chemistry, 2 , — Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway.

    Nature Immunology, 6 8 , — Deneris, E. Identification of a gene proposed to encode a non-alpha subunit of neuronal nicotinic acetylcholine receptors. Clinical Chemistry , 35 5 , — Dent, J. The evolution of pentameric ligand-gated ion channels. Advances in Experimental Medicine and Biology, , 11— Descarries, L. Diffuse transmission by acetylcholine in the CNS. Progress in Neurobiology, 53 5 , — Dunn, S. Activation and desensitization of Torpedo acetylcholine receptor: Evidence for separate binding sites. Duvoisin, R. The functional diversity of the neuronal nicotinic acetylcholine receptors is increased by a novel subunit: beta 4.

    Neuron , 3 4 , — Egea, J. Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection. Biochemical Pharmacology, 97 4 , — Eldefrawi, M. Activation, inactivation, and desensitization of acetylcholine receptor channel complex detected by binding of perhydrohistrionicotoxin. Elgoyhen, A. Cell, 79 , — Alpha A determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells.

    Etter, J. Cytisine for smoking cessation: A research agenda. Drug and Alcohol Dependency, 92 1—3 , 3—8. Fatt, P. An analysis of the endplate potential recorded with an intra-cellular electrode. Feldberg, W. The cholinergic nature of the nerves to the electric organ of the Torpedo Torpedo marmorata. Journal of Physiology, 2 , — Fonck, C. Demonstration of functional alpha4-containing nicotinic receptors in the medial habenula.

    Neuropharmacology, 56 1 , — Forsayeth, J. Formation of Oligomers containing the beta3 and beta4 subunits of the rat nicotinic receptor. Journal of Neuroscience, 17 5 , — Francis, M. Sensitivity to voltage-independent inhibition determined by pore-lining region of ACh receptor. Biophysical Journal, 74 5 , — Muscle-type nicotinic acetylcholine receptor delta subunit determines sensitivity to noncompetitive inhibitors while gamma subunit regulates divalent permeability. Neuropharmacology, 35 11 , — Froehner, S. The submembrane machinery for nicotinic acetylcholine receptor clustering.

    Journal of Cell Biology, 1 , 1—7. Galzi, J. Mutations in the channel domain of a neuronal nicotinic receptor convert ion selectivity from cationic to anionic. Gault, J. Comparison of polymorphisms in the alpha7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects. Gerzanich, V.

    Background

    Molecular Pharmacology, 51 , — Journal of Pharmacology and Experimental Therapeutics, 1 , — Gill, J. Gill-Thind, J. Structurally similar allosteric modulators of alpha7 nicotinic acetylcholine receptors exhibit five distinct pharmacological effects. Journal of Biological Chemistry, 6 , — Gotti, C. Alpha7 and alpha8 nicotinic receptor subtypes immunopurified from chick retina have different immunological, pharmacological and functional properties.

    European Journal of Neuroscience, 9 6 , — Grady, S. The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum. Biochemical Pharmacology, 74 8 , — Gronlien, J. Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes. Molecular Pharmacology, 72 3 , — Gu, S. Neuron, 89 5 , — Gunthorpe, M. Conversion of the ion selectivity of the 5-HT 3a receptor from cationic to anionic reveals a conserved feature of the ligand-gated ion channel superfamily.

    Journal of Biological Chemistry, 24 , — Haghighi, A. A molecular link between inward rectification and calcium permeability of neuronal nicotinic acetylcholine alpha3beta4 and alpha4beta2 receptors. Journal of Neuroscience, 20 2 , — Halevi, S. The C. EMBO Journal, 21 5 , — Han, Z. European Journal of Neuroscience, 12 10 , — Localization of [3H]nicotine, [3H]cytisine, [3H]epibatidine, and [I]alpha-bungarotoxin binding sites in the brain of Macaca mulatta. Journal of Comparative Neurology, 1 , 49— Hansen, S.

    Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations. EMBO Journal, 24 20 , — Hauser, T. TC An alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia. Biochemical Pharmacology, 78 7 , — Haydar, S.

    Current Topics in Medicinal Chemistry, 10 2 , — Heidmann, T. Characterisation of the transient agonist-triggered state of the acetylcholine receptor rapidly labeled by the non-competitive blocker [ 3 H]chlorpromazine: Additional evidence for the open channel conformation. Biochemistry, 25 , — Hilf, R.

    X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Hodgkin, A. A quantitative description of membrane current and its application to conduction and excitation in nerve. Holden-Dye, L. Nicotinic acetylcholine receptors: A comparison of the nAChRs of Caenorhabditis elegans and parasitic nematodes. Parasitology International, 62 6 , — Hollmann, M. Cloning by functional expression of a member of the glutamate receptor family.

    Horenstein, N. Multiple pharmacophores for the selective activation of nicotinic alpha7-type acetylcholine receptors. Molecular Pharmacology, 74 6 , — Reversal of agonist selectivity by mutations of conserved amino acids in the binding site of nicotinic acetylcholine receptors. Journal of Biological Chemistry, 8 , — Critical molecular determinants of alpha7 nicotinic acetylcholine receptor allosteric activation: Separation of direct allosteric activation and positive allosteric modulation.

    Journal of Biological Chemistry, 10 , — Cracking the betel nut: Cholinergic activity of Areca alkaloids and related compounds. Nicotine and Tobacco Research , in press. Horn, R. Statistical properties of single sodium channels. Journal of General Physiology, 84 4 , — Hucho, F. Photoaffinity derivatives of alpha-bungarotoxin and alpha-Naja naja siamensis toxin.

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    Nicotinic Acetylcholine Receptors

    PLoS One, 11 3 , e Janin, J. Protein flexibility, not disorder, is intrinsic to molecular recognition. F Biology Reports, 5 , 2. Jeanclos, E. The chaperone protein eta interacts with the nicotinic acetylcholine receptor alpha 4 subunit. Evidence for a dynamic role in subunit stabilization. Journal of Biological Chemistry, 30 , — Jiang, L. Cholinergic signaling controls conditioned fear behaviors and enhances plasticity of cortical-amygdala circuits.

    Neuron, 90 5 , — Jones, A. Insect nicotinic acetylcholine receptor gene families: From genetic model organism to vector, pest and beneficial species. Invertebrate Neuroscience, 7 1 , 67— Kao, P. Acetylcholine receptor binding site contains a disulfide cross-link between adjacent half-cystinyl residues. Journal of Biological Chemistry, 18 , — Karlin, A. Facets of the structures of acetylcholine receptors from Electrophorus and Torpedo. Katz, B. The statistical nature of the acetylcholine potential and its molecular components. Journal of Physiology, , 63— Kem, W.

    Pharmacokinetic limitations on effects of an alpha7 nicotinic receptor agonist in schizophrenia: Randomized trial with an extended release formulation. Neuropsychopharmacology , in press. Keramidas, A. M2 pore mutations convert the glycine receptor channel from being anion- to cation-selective.

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    Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery. Levin, E. Nicotinic effects on cognitive function: Behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology Berlin , 3—4 , — Li, S. Ligand-binding domain of an alpha7-nicotinic receptor chimera and its complex with agonist. Nature Neuroscience, 14 10 , — Li, X. Archives of Gerontology and Geriatrics, 61 3 , — Liebeskind, B.

    Convergence of ion channel genome content in early animal evolution. Lindsley, C. ACS Chemical Neuroscience, 1 8 , — Liu, Q. Functional alpha7beta2 nicotinic acetylcholine receptors expressed in hippocampal interneurons exhibit high sensitivity to pathological level of amyloid beta peptides. BMC Neuroscience, 13 , Loewi, O. On the background of the discovery of neurochemical transmission.

    Journal of Mt. Sinai Hospital, New York, 24 6 , — Luetje, C. Both a- and b-subunits contribute to the agonist sensitivity of neuronal nicotinic acetylcholine receptors. Journal of Neuroscience, 11 3 , — Margiotta, J. The properties and regulation of functional acetylcholine receptors on chick ciliary ganglion neurons. Journal of Neuroscience, 7 , — Martin, E. Cytoprotective actions of 2,4-dimethoxybenzylidene anabaseine in differentiated PC12 cells and septal cholinergic cells. Drug Development Research, 31 , — McClure-Begley, T. Exploring the nicotinic acetylcholine receptor-associated proteome with iTRAQ and transgenic mice.

    Genomics Proteomics Bioinformatics, 11 4 , — McGehee, D. Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. McQueen, E. Use of mecamylamine in the management of hypertension. British Medical Journal, 1 , — Merlie, J. Denervation supersensitivity in skeletal muscle: Analysis with a cloned cDNA probe. Journal of Cell Biology, 99 , — Methfessel, C. Patch clamp measurements on Xenopus laevis oocytes: Currents through endogenous channels and implanted acetylcholine receptor and sodium channels. Meyer, E. Effects of anabaseine-related analogs on rat brain nicotinic receptor binding and on avoidance behaviors.

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    Local anaesthetics transiently block current through single acetylcholine receptor channels. Noda, M.

    Types of neurotransmitters - Nervous system physiology - NCLEX-RN - Khan Academy

    Cloning and sequence analysis of calf cDNA and human genomic DNA encoding alpha-subunit precursor of muscle acetylcholine receptor subunits. Primary structure of alpha-subunit precursor of Torpedo californica acetylcholine receptor deduced from cDNA sequence.

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