(alpha4)_2(beta2)_3 nAChR [DA:0000027]

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Creation Date
2003-01-05T00:00:00
Last Modification Date
2004-09-02T15:49:41
Structure Generic Properties Distribution Function Maintainers Contributors References
Structure
Components
2 X alpha4 nicotinic receptor subunit [DA:0000188]
Ligand-Gated Ion Channel database Homo sapiens (1)
InterPro Homo sapiens
Ligand-Gated Ion Channel database Mus musculus (3)
Ligand-Gated Ion Channel database Rattus norvegicus (4)
3 X beta2 nicotinic receptor subunit [DA:0000186]
Ligand-Gated Ion Channel database Homo sapiens (5)
InterPro Homo sapiens
Ligand-Gated Ion Channel database Mus musculus (7)
Ligand-Gated Ion Channel database Rattus rattus (6)
States
basal In the basal state, the ionic pore is closed. This state displays a weak affinity for agonists such as acetylcholine or nicotine.
active In the active state, the ionic pore is open. This state displays a higher affinity for agonists than the basal state.
desensitized In the desensitized state, the ionic pore is open. This state displays the highest affinity for desensitizing agonists (e.g. acetylcholine, nicotine) and antagonists.
Generic Properties
basal MW 310971 Daltonwithout covalent modifications.
Homo sapiens
Distribution
mesencephalic dopaminergic neuron
cell soma [DA:0000137]
in situ hybridisation Labelling for alpha4 and beta2 are both medium to strong Rattus norvegicus (8, 16)
single cell RT-PCR a4 is present in 100% of neurons. b2 is probably also present in 100% of neurons. Rattus norvegicus (17)
in situ hybridisation Labelling for both alpha4and beta2 is strong Macaca mulatta (2)
immunopurification a4b2, alone or together with a5 or b3, forms 80% of the nAChRs located in the somato-dendritic compartment of the mecencephalic DA neurons. Mus musculus (9)
terminal button [DA:0000006]
immunopurification a4b2, alone or together with a6 and or b3, forms 50% of the nAChRs on the dopaminergic terminals of the mecencephalic DA neurons in the striatum. Mus musculus (9)
immunopurification a4b2, alone or together with a6 and or b3, forms 50% of the nAChRs on the dopaminergic terminals of the mecencephalic DA neurons in the striatum. Rattus norvegicus (10)
striatal enkephalinergic/GABAergic medium spiny neuron
cell soma [DA:0000137]
in situ hybridisation Labelling for beta2 is medium. Labelling for alpha4 is undetectable Rattus norvegicus (8)
in situ hybridisation Labelling for beta2 is medium. Alpha4 is undetectable Macaca mulatta (2)
striatal substance p/GABAergic medium spiny neuron
cell soma [DA:0000137]
in situ hybridisation Labelling for beta2 is medium. Labelling for alpha4 is undetectable Rattus norvegicus (8)
in situ hybridisation Labelling for beta2 is medium. Alpha4 is undetectable. Macaca mulatta (2)
Function
Binding
epibatidine
nAChRa4_2b2_3 desensitized Kd 41 ± 11.3 picomole per litre
Rattus norvegicus (10, 18) Values of Zoli et al (2002) are favoured over those of Parker et al (1998) because the former are recorded from receptor coming from DA neurons while the latter are recorded in Xenopus oocytes. However, values are comparable since Parker et al (1998) found mean="30.0" sd="3.9".
nAChRa4_2b2_3 desensitized Kd 33.4 ± 6 picomole per litre
Homo sapiens (11) Expression in HEK293
nAChRa4_2b2_3 desensitized Kd 10 ± 1.4 picomole per litre
Homo sapiens (19) expression in SH-EP1
nAChRa4_2b2_3 desensitized kon 12.3 ± 0.33 litre per micromole second
Homo sapiens (19)
nAChRa4_2b2_3 desensitized koff 0.013 ± 0.001 reciprocal minute
Homo sapiens (19)
acetylcholine [DA:0000184]
nAChRa4_2b2_3 active EC50 65.6 ± 28.6 micromole per litre
Rattus norvegicus (12) The EC50 can be seen as a first approximation of the Kd for the active state.
nAChRa4_2b2_3 active EC50 26.7 ± 6.1 micromole per litre
Homo sapiens (11) EC50 can be seen as an approximation of the Kd in the active state. Values of Chavez-Noriega et al 2000 are favoured over Chavez-Noriega et (1997) because recording come from HEK cells and not oocytes.
nAChRa4_2b2_3 desensitized Ki_epibatidine 8.6 ± 1.98 nanomole per litre
Rattus norvegicus (10, 18) Values of Zoli et al (2002) are favoured over those of Parker et al (1998) because the former are recorded from receptor coming from DA neurons while the latter are recorded in Xenopus oocytes. Parker et al (1998) found 34+-6.6 nM.
nAChRa4_2b2_3 desensitized Ki_epibatidine 18 nanomole per litre
Homo sapiens (19)
nicotine
nAChRa4_2b2_3 desensitized Ki_epibatidine 1.75 ± 0.4 nanomole per litre
Rattus norvegicus (10, 18) Values of Zoli et al (2002) are favoured over those of Parker et al (1998) because the former are recorded from receptor coming from DA neurons while the latter are recorded in Xenopus oocytes. Parker et al (1998) found mean="4.6" sd="0.33".
nAChRa4_2b2_3 active EC50 5.52 ± 0.73 micromole per litre
Homo sapiens (13) The EC50 can be a first approximation of the Kd in the active state.
nAChRa4_2b2_3 desensitized Ki_epibatidine 1.98 nanomole per litre
Homo sapiens (19)
nAChRa4_2b2_3 desensitized Kd 0.4 ± 0.01 nanomole per litre
Rattus norvegicus (20) Expressed in HEK293
cytisine
nAChRa4_2b2_3 desensitized Ki_epibatidine 0.24 nanomole per litre
Homo sapiens (19)
nAChRa4_2b2_3 desensitized Kd 0.12 ± 0.005 nanomole per litre
Rattus norvegicus (20) Expressed in HEK293
di-hydro beta erythridine
nAChRa4_2b2_3 desensitized Ki_cytisine 20 nanomole per litre18-25 nM according to the concentration of cytisine.
Rattus norvegicus (20)
Enzymatic function
Permeability
cation [DA:0000264]
nAChRa4_2b2_3 active conductance 42.2 picosiemens
Homo sapiens (15)
nAChRa4_2b2_3 active conductance 13.3 ± 1.5 picosiemens
Rattus norvegicus (14)
Modulated
Transitions
transition from basal to transition from active () In the absence of ligand, the equilibrium is strongly displaced toward the basal state. Agonists, such as acetylcholine and nicotine, stabilise the active state and shift the equilibrium. The transition from basal to active corresponds to an opening of the ionic pore.
transition from active to transition from desensitized () Desensitizing agonists and antagonists display a higher affinity for the desensitized than for the active state, and shift the equilibrium toward the former one.
Maintainers
Nicolas Le Novère Computational Neurobiology, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton Cambridge, CB10 1SD United-Kingdom
Contributors
Nicolas Le Novère Computational Neurobiology, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton Cambridge, CB10 1SD United-Kingdom
References
1 Monteggia,L.M., Gopalakrishnan,M., Touma,E., Idler,K., Nash,N., Arneric,S.P., Sullivan,J.P. and Giordano,T. The cloning and transient expression of the human alpha4 and beta2 neuronal nicotinic acetylcholine receptor (nAChR) subunits. Gene 1995 155:189-193 [pubmed]
2 Han Z.-Y., Le Novère N., Zoli M., Champtiaux N., Hill J.A., Changeux J.-P. (2000). localization of nAChR subunit mRNAs in the brain of Macaca mulatta. European Journal of Neuroscience 12: 3664-3674. [pubmed]
3 Stitzel,J.A., Jimenez,M., Smolen,A. and Modir,J. Cloning of mouse nicotinic acetylcholine receptor subunit alpha4 cDNA. Unpublished
4 Goldman,D.J., Deneris,E.S., Luyten,W., Kochhar,A., Patrick,J. and Heinemann,S.F. Members of a nicotinic acetylcholine receptor gene family are expressed in different regions of the mammalian central nervous systems. Cell 48, 965-973 (1987) [pubmed]
5 Anand,R. and Lindstrom,J. Nucleotide sequence of the human nicotinic acetylcholine receptor beta 2 subunit gene Nucleic Acids Res. 18 (14), 4272 (1990) [pubmed]
6 Boulter,J., Connolly,J., Deneris,E.S., Goldman,D.J., Heinemann,S.F. and Patrick,J. Functional expression of two neuronal nicotinic acetylcholine receptors from cDNA clones identifies a gene family. Proc. Natl. Acad. Sci. U.S.A. 84, 7763-7767 (1987) [pubmed]
7 Lueders K.K., Elliott R.W., Marenholz I., Mischke D., DuPree M., Hamer D. "Genomic organization and mapping of the human and mouse neuronal beta2-nicotinic acetylcholine receptor genes". Mamm. Genome 10(9):900-905(1999). [pubmed]
8 Wada E., Wada K., Boulter J., Deneris E., Heinemann S., Patrick J., Swanson LW (1989). Distribution of Alpha2, Alpha3, Alpha4, and Beta2 neuronal nicotinic subunit mRNAs in the central nervous system: a hybridization histochemical study in rat. Journal of Comparative Neurology, 284: 314-335. [pubmed]
9 Champtiaux N., Gotti C., Cordero-Erausquin M., David D., Przybylski C., Léna C., Clementi F, Moretti M, Rossi FM, Le Novère N, McInstosh J.M., Gardier A.M., Changeux J.-P. Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knockout mice. J Neurosci. 2003 Aug 27;23(21):7820-9. [pubmed]
10 Zoli M, Moretti M, Zanardi A, McIntosh JM, Clementi F, Gotti C (2002). Identification of the nicotinic receptor subtypes expressed on dopaminergic terminals in the rat striatum. J Neurosci 22:8785-8789 [pubmed]
11 Chavez-Noriega LE, Gillespie A, Stauderman KA, Crona JH, Claeps BO, Elliott KJ, Reid RT, Rao TS, Velicelebi G, Harpold MM, Johnson EC, Corey-Naeve J. (2000) Characterization of the recombinant human neuronal nicotinic acetylcholine receptors alpha3beta2 and alpha4beta2 stably expressed in HEK293 cells. Neuropharmacology 39:2543-60 [pubmed]
12 Zwart R, Vijverberg HP (1998). Four pharmacologically distinct subtypes of alpha4beta2 nicotinic acetylcholine receptor expressed in Xenopus laevis oocytes. Mol. Pharmacol., 54: 1124-1131. [pubmed]
13 Chavez-Noriega LE, Crona JH, Washburn MS, Urrutia A, Elliott KJ, Johnson EC. (1997) Pharmacological characterization of recombinant human neuronal nicotinic acetylcholine receptors halpha2beta2, halpha2beta4, halpha3beta2, halpha3beta4, halpha4beta2, halpha4beta4 and halpha7. J Pharmacol Exp Ther 280:346-56 [pubmed]
14 Papke RL, Boulter J, Patrick J, Heinemann S. (1989). Single-channel currents of rat neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes. Neuron, 3: 589-596 [pubmed]
15 Buisson B, Picard F, Bertrand D. (2000). Neuronal nicotinic acetylcholine receptors: from biophysical properties to human diseases. In: Neuronal nicotinic receptors, Clementi, Fornasari and Gotti. Springer, pp 271-299.
16 Le Novère N, Zoli M, Changeux JP (1996). Neuronal nicotinic receptor a6 subunit mRNA is selectively concentrated in catecholaminergic nuclei of the rat brain. European Journal of Neuroscience, 8: 2428-2439. [pubmed]
17 Klink R, de Kerchove d'Exaerde A, Zoli M, Changeux JP. Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J Neurosci. 2001 Mar 1;21(5):1452-63. [pubmed]
18 Parker MJ, Beck A, Luetje CW. Neuronal nicotinic receptor beta2 and beta4 subunits confer large differences in agonist binding affinity. Mol Pharmacol. 1998 Dec;54(6):1132-9. [pubmed]
19 Eaton JB, Peng JH, Schroeder KM, George AA, Fryer JD, Krishnan C, Buhlman L, Kuo YP, Steinlein O, Lukas RJ. Characterization of human alpha4 beta2-nicotinic acetylcholine receptors stably and heterologously expressed in native nicotinic receptor-null SH-EP1 human epithelial cells. Mol Pharmacol. 2003 Dec;64(6):1283-94. [pubmed]
20 Sabey K, Paradiso K, Zhang J, Steinbach JH. Ligand binding and activation of rat nicotinic alpha4beta2 receptors stably expressed in HEK293 cells. Mol Pharmacol. 1999 Jan;55(1):58-66. [pubmed]