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20-September-2008 09:55:56 - acetylcholine receptor Acetylcholine Acetylcholine Nicotine Nicotine Acetylcholine receptor nicotinic from electric torpedo rays very similar to human receptor is made of 5 subunits, 2 of which shown in orange bind ACh red. Structure was determined by electron crystallography at 4 Ã… resolution PDB code: 2bg9 more details... Acetylcholine receptor nicotinic from electric torpedo rays very similar to human receptor is made of 5 subunits, 2 of which shown in orange bind ACh red. Structure was determined by electron crystallography at 4 Ã… resolution PDB code: 2bg9 more details... Acetylcholine receptor blocked by cobra venom PDB code: 1yi5. A similar effect can be achieved by high doses of curare or nicotine more details... Acetylcholine receptor blocked by cobra venom PDB code: 1yi5. A similar effect can be achieved by high doses of curare or nicotine more details... Nicotinic acetylcholine receptors, or nAChRs, are Cholinergic receptors that form ligand-gated ion channels in cells' plasma membranes. Like the other type of acetylcholine receptors, muscarinic acetylcholine receptors mAChRs, their opening is triggered by the neurotransmitter acetylcholine ACh, but they are also opened by nicotine.12 Also in contrast to muscarinic ACh receptors, nicotinic receptors do not operate with a second messenger, but open themselves forming an ion channel. Their action is inhibited by curare. Nicotinic acetylcholine receptors are present in many tissues in the body. The neuronal receptors are found in the central nervous system and the peripheral nervous system. The neuromuscular receptors are found in the neuromuscular junctions of somatic muscles; stimulation of these receptors causes muscular contraction. Contents 1 Structure 2 Opening the channel 3 Effects 4 Receptor regulation 4.1 Receptor desensitization 5 Roles 6 Subunits 6.1 Notable variations 7 References 8 External links Structure Nicotinic receptors, with a molecular mass of 290 kDa 3, are made up of five receptor subunits, arranged symmetrically around the central pore. They share similarities with GABAA receptors, glycine receptors, and the type 3 serotonin receptors, which are all therefore classed in the ionotropic family, or the signature Cys-loop proteins.4 Twelve types of nicotinic receptor subunits, α2 through 10 and β2 through 4 Itier and Bertrand, 2001, combine to form pentamers. The subunits are somewhat similar to one another, especially in the hydrophobic regions.1 The muscle form of the nAChR consist of two α subunits, a β, a δ and either a γ or an ε.125 The neuronal forms are much more heterogeneous, with a wide range of possible subunit combinations. The sites for binding ACh are on the outside of the α subunits near their N termini.1When the agonist binds, the α subunits become more similar to the other subunits, the channel becomes more symmetrical,6 and a pore with a diameter of about 0.65 nm opens.1 Opening the channel Nicotinic AChRs may exist in different interconvertible conformational states. Binding of an agonist stabilizes the open and desensitised states. Opening of the channel allows positively charged ions, in particular, sodium and potassium, to enter the cell. The nAChR is permeable to Na+ and K+, with some subunit combinations that are also permeable to Ca2+.1 The amount of sodium and potassium the channels allow through their pores their conductance varies from 50-110 pS, with the conductance depending on the specific subunit composition as well as the permeant ion.7 Interestingly, because some neuronal nAChRs are permeable to Ca2+, they can affect the release of other neurotransmitters.2 The channel usually opens rapidly and tends to remain open until the agonist diffuses away, usually for about 1 millisecond.1 However, AChRs can open sometimes with only one agonist bound and in rare cases with no agonist bound, and they can close spontaneously even when ACh is bound, so ACh binding only creates a probability of pore opening, which increases as more ACh binds.6 Effects This activation of receptors by nicotine modifies the state of neurons through two main mechanisms. On one hand, the movements of cations cause a depolarization of the plasma membrane, which results in an excitation, particularly of neurons, but also by the activation of other voltage-gated ion channels. On the other hand, the entry of calcium acts, either directly or indirectly, on different intracellular cascades leading, for example, to the regulation of the activity of some genes or the release of neurotransmitters. Receptor regulation Receptor desensitization Ligand-bound desensitization of receptors was first characterized by Katz and Thesleff in the nicotinic acetylcholine receptor8 Prolonged or repeat exposure to a stimulus often results in decreased responsiveness of that receptor for a stimulus. nAChR function can be modulated by phosphorylation9 by the activation of second messenger-dependent protein kinases. Phosphorylation of the nAChR by PKA8 and PKC10 have been shown to phosphorylate nAChR resulting in its desensitization. It has been reported that after prolonged receptor exposure to the agonist, the agonist itself causes an agonist-induced conformational change in the receptor, resulting in receptor desensitization.11 This receptor desensitization has been previously modeled in the context of a two-state mathematical model see this link 1 Roles The subunits of the nicotinic receptors belong to a multigene family 17 members in human and the assembly of combinations of subunits results in a large number of different receptors For more information see the Ligand-Gated Ion Channel database. These receptors, with highly variable kinetic, electrophysiological and pharmacological properties, respond differently to nicotine, at very different effective concentrations. This functional diversity allows them to take part in two major types of neurotransmission. Classical synaptic transmission wiring transmission involves the release of high concentrations of neurotransmitter, acting on immediately neighbouring receptors. In contrast, paracrine transmission volume transmission involves neurotransmitters released by synaptic buttons or varicosities, which then diffuse through the extra-cellular medium until they reach their receptors, which may be distant. Nicotinic receptors can also be found in different synaptic locations, for example the muscle nicotinic receptor always functions post-synaptically. The neuronal forms of the receptor can be found both post-synaptically involved in classical neurotransmission and pre-synaptically where they can influence the release of other neurotranmsitters. Subunits To date 17 nAChR subunits have been identified, these are divided into muscle-type and neuronal-type subunits. Of these 17 subunits, α2-α7 and β2-β4 have been cloned in humans, the remaining genes identified in chick and rat genomes.12 The nAChR subunits have been divided into 4 subfamilies I-IV based on similarities in protein sequence 13. In addition, subfamily III has been further divided into 3 tribes. Neuronal-type Muscle-type I II III IV α9, α10 α7, α8 1 2 3 α1, β1, δ, γ, ε α2, α3, α4, α6 β2, β4 β3, α5 Alpha genes: CHRNA1 muscle, CHRNA2 neuronal, CHRNA3, CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNA8, CHRNA9, CHRNA10 Beta genes: CHRNB1 muscle, CHRNB2 neuronal, CHRNB3, CHRNB4, Other genes: CHRND delta, CHRNE epsilon, CHRNG gamma Notable variations Nicotinic receptors are pentamers of these subunits, i.e. each receptor contains five subunits. Thus, there is an immense potential of variation of the aforementioned subunits. However, some of them are more notable than others, specifically α12β1δε muscle type, α32β43 ganglion type, α42β23 CNS type and α75 another CNS type.14 A comparison follows: Receptor type Location Effect Nicotinic agonists Antagonists Muscle type: α12β1δε14 or α1β1δγε15 Neuromuscular junction EPSP, mainly by increased Na+ and K+ permeability acetylcholine carbachol suxamethonium α-bungarotoxin15 α-conotoxin tubocurarine pancuronium Ganglion type: α32β43 autonomic ganglia EPSP, mainly by increased Na+ and K+ permeability acetylcholine carbachol nicotine epibatidine dimethylphenylpiperazinium varenicline α-bungarotoxin15 mecamylamine trimetaphan hexamethonium bupropion dextromethorphan ibogaine 18-methoxycoronaridine CNS type: α42β23 Brain Post- and presynaptic excitation,14 mainly by increased Na+ and K+ permeability nicotine epibatidine acetylcholine cytisine mecamylamine methylcaconitine α-conotoxin another CNS type: α75 Brain Post- and presynaptic excitation,14 mainly by increased Ca2+ permeability epibatidine dimethylphenylpiperazinium mecamylamine α-bungarotoxin References ^ a b c d e f g Siegel G.J., Agranoff B.W., Fisher S.K., Albers R.W., and Uhler M.D. 1999. Basic Neurochemistry: Molecular, Cellular and Medical Aspects, Sixth ion. GABA Receptor Physiology and Pharmacology. American Society for Neurochemistry. Lippincott Williams and Wilkins. Available. ^ a b c Itier V. and Bertrand D. 2001. Neuronal nicotinic receptors: from protein structure to function. ed by Andreas Engel and Giorgio Semenza. FEBS Letters, 5043, 118-125. ^ Unwin N. 2005. Refined Structure of the Nicotinic Acetylcholine Receptor at 4A Resolution. J Mol Biol 2005 346,967-989. ^ Cascio, M. 2004. Structure and function of the glycine receptor and related nicotinicoid receptors. Journal of Biological Chemistry, 27919, 19383-19386. Available. ^ Giniatullin R., Nistri A., and Yakel J.L. 2005. Desensitization of nicotinic ACh receptors: shaping cholinergic signaling. Trends in Neurosciences, 287, 371-378. ^ a b Colquhoun D. and Sivilotti L.G. 2004. Function and structure in glycine receptors and some of their relatives. Trends in Neurosciences, 276, 337-344. ^ Mishina M., Takai T., Imoto K., Noda M., Takahashi T., Numa S., Methfessel C., and Sakmann B. 1986 Molecular distinction between fetal and adult forms of muscle acetylcholine receptor. Nature, 321: 406-411. ^ a b S. Pitchford, J.W. Day, A. Gordon and D. Mochly-Rosen. 1992 Acetylcholine receptor desensitization is Regulated by activation-induced extracellular adenosine accumulation. The Journal of Neuroscience, 1.311: 4540-4544. ^ R.L. Huganir, P. Greengard. 1983 CAMP-dependent protein kinase phosphorylates the nicotinic acetylcholine receptor. Proc Nat1 Acad Sci USA 80: 1130-l 134. ^ A. Safran, R. Sagi-Eisenbeg, D. Neumann, S. Fuchs 1987 Phosphorylation of the acetylcholine receptor by protein kinase C and identification of the phosphorylation site within the receptor δ subunit. J Biol Chem 262:10506-10510. ^ F.J. Barrantes. 1978 Agonist-mediated changes of the acetylcholine receptor in its membrane environment. J Mol Biol 124: l-26. ^ Graham A., Court J.A., Martin-Ruiz C.M., Jaros E., Perry R., Volsen S.G., Bose S., Evans N., Ince P., Kuryatov A., Lindstrom J., Gotti C., and Perry E.K. 2002. Immunohistochemical localisation of nicotinic acetylcholine receptor subunits in human cerebellum. Neuroscience, 1133, 493-507. ^ Le Novère N, Changeux J.P 1995. Molecular evolution of the nicotinic acetylcholine receptor: an example of multigene family in excitable cells. Journal of Molecular Evolution, 40, 155-172. ^ a b c d Pharmacology, Rang, Dale, Ritter Moore, ISBN 0443071454, 5:th ed., Churchill Livingstone 2003 Page 138. ^ a b c Neurosci.pharm - MBC 3320 Acetylcholine External links Wikiversity At Wikiversity, you can learn about: Poisson-Boltzmann profile for an ion channel Calculated spatial position of Nicotinic acetylcholine receptor in the lipid bilayer v d e Antigens: Autoantigens Dehydrogenase Branched-chain alpha-keto acid dehydrogenase complex - Oxoglutarate dehydrogenase - Pyruvate dehydrogenase Transglutaminase Epidermal transglutaminase - Tissue transglutaminase Nucleoporins Nucleoporin-62 - Nucleoporin-210 Other Acetylcholine receptor - Actin - Apolipoprotein H - Cardiolipin - Centromere - FilaggrinCitrullinate - Gangliosides - Sp100 nuclear antigen - Thrombin - Topoisomerase v d e Ion channel, receptor: ligand-gated ion channels Cys-loop receptors 5-HT/serotonin 5-HT3 A, B, C, D, E GABA GABA A α1, α2, α3, α4, α5, α6, β1, β2, β3, γ1, γ2, γ3, δ, ε, Ï€, θ GABA C Ï?1, Ï?2, Ï?3 Glycine α1, α2, α3, α4, β Nicotinic acetylcholine monomers: α1, α2, α3, α4, α5, α6, α7, α9, α10, β1, β2, β3, β4, δ, ε pentamers: α42β23, α75, α12β43 - Ganglion type, α12β1δε - Muscle type Ionotropic glutamates AMPA 1, 2, 3, 4 Kainate 1, 2, 3, 4, 5 NMDA 1, 2A, 2B, 2C, 2D, 3A, 3B, L1A, L1B ATP-gated channels Purinergic receptors: P2X 1, 2, 3, 4, 5, 6, 7 Retrieved from http://en..org/wiki/Nicotinic_acetylcholine_receptor Categories: Ion channels | Ionotropic receptors | Neurotransmitters | Autoantigens | Cell signaling Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Deutsch Español Français Italiano Polski Português УкраїнÑ?ька This page was last modified on 9 August 2008, at 13:22
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