Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Cell Mol Life Sci
2021 Feb 01;783:1051-1064. doi: 10.1007/s00018-020-03558-z.
Show Gene links
Show Anatomy links
Concatemers to re-investigate the role of α5 in α4β2 nicotinic receptors.
Prevost MS
,
Bouchenaki H
,
Barilone N
,
Gielen M
,
Corringer PJ
.
???displayArticle.abstract???
Nicotinic acetylcholine receptors (nAChRs) are pentameric ion channels expressed in the central nervous systems. nAChRs containing the α4, β2 and α5 subunits are specifically involved in addictive processes, but their functional architecture is poorly understood due to the intricacy of assembly of these subunits. Here we constrained the subunit assembly by designing fully concatenated human α4β2 and α4β2α5 receptors and characterized their properties by two-electrodes voltage-clamp electrophysiology in Xenopus oocytes. We found that α5-containing nAChRs are irreversibly blocked by methanethiosulfonate (MTS) reagents through a covalent reaction with a cysteine present only in α5. MTS-block experiments establish that the concatemers are expressed in intact form at the oocyte surface, but that reconstitution of nAChRs from loose subunits show inefficient and highly variable assembly of α5 with α4 and β2. Mutational analysis shows that the concatemers assemble both in clockwise and anticlockwise orientations, and that α5 does not contribute to ACh binding from its principal (+) site. Reinvestigation of suspected α5-ligands such as galantamine show no specific effect on α5-containing concatemers. Analysis of the α5-D398N mutation that is linked to smoking and lung cancer shows no significant effect on the electrophysiological function, suggesting that its effect might arise from alteration of other cellular processes. The concatemeric strategy provides a well-characterized platform for mechanistic analysis and screening of human α5-specific ligands.
Absalom,
Functional genomics of epilepsy-associated mutations in the GABAA receptor subunits reveal that one mutation impairs function and two are catastrophic.
2019, Pubmed,
Xenbase
Absalom,
Functional genomics of epilepsy-associated mutations in the GABAA receptor subunits reveal that one mutation impairs function and two are catastrophic.
2019,
Pubmed
,
Xenbase
Ahring,
Concatenated nicotinic acetylcholine receptors: A gift or a curse?
2018,
Pubmed
,
Xenbase
Benallegue,
The additional ACh binding site at the α4(+)/α4(-) interface of the (α4β2)2α4 nicotinic ACh receptor contributes to desensitization.
2013,
Pubmed
,
Xenbase
Besson,
Profound alteration in reward processing due to a human polymorphism in CHRNA5: a role in alcohol dependence and feeding behavior.
2019,
Pubmed
Besson,
Alterations in alpha5* nicotinic acetylcholine receptors result in midbrain- and hippocampus-dependent behavioural and neural impairments.
2016,
Pubmed
Carbone,
Pentameric concatenated (alpha4)(2)(beta2)(3) and (alpha4)(3)(beta2)(2) nicotinic acetylcholine receptors: subunit arrangement determines functional expression.
2009,
Pubmed
,
Xenbase
Dawson,
Knockout of alpha 5 nicotinic acetylcholine receptors subunit alters ethanol-mediated behavioral effects and reward in mice.
2018,
Pubmed
Eaton,
The unique α4+/-α4 agonist binding site in (α4)3(β2)2 subtype nicotinic acetylcholine receptors permits differential agonist desensitization pharmacology versus the (α4)2(β2)3 subtype.
2014,
Pubmed
,
Xenbase
Exley,
Striatal α5 nicotinic receptor subunit regulates dopamine transmission in dorsal striatum.
2012,
Pubmed
Forget,
A Human Polymorphism in CHRNA5 Is Linked to Relapse to Nicotine Seeking in Transgenic Rats.
2018,
Pubmed
Fowler,
Habenular α5 nicotinic receptor subunit signalling controls nicotine intake.
2011,
Pubmed
George,
Function of human α3β4α5 nicotinic acetylcholine receptors is reduced by the α5(D398N) variant.
2012,
Pubmed
,
Xenbase
George,
Isoform-specific mechanisms of α3β4*-nicotinic acetylcholine receptor modulation by the prototoxin lynx1.
2017,
Pubmed
,
Xenbase
Gharpure,
Agonist Selectivity and Ion Permeation in the α3β4 Ganglionic Nicotinic Receptor.
2019,
Pubmed
Gielen,
Benzodiazepines modulate GABAA receptors by regulating the preactivation step after GABA binding.
2012,
Pubmed
,
Xenbase
Grady,
Mouse striatal dopamine nerve terminals express alpha4alpha5beta2 and two stoichiometric forms of alpha4beta2*-nicotinic acetylcholine receptors.
2010,
Pubmed
Groot-Kormelink,
Constraining the expression of nicotinic acetylcholine receptors by using pentameric constructs.
2006,
Pubmed
,
Xenbase
Hamouda,
Photolabeling a Nicotinic Acetylcholine Receptor (nAChR) with an (α4)3(β2)2 nAChR-Selective Positive Allosteric Modulator.
2016,
Pubmed
,
Xenbase
Hannan,
Cell surface expression of homomeric GABAA receptors depends on single residues in subunit transmembrane domains.
2018,
Pubmed
Jain,
Unorthodox Acetylcholine Binding Sites Formed by α5 and β3 Accessory Subunits in α4β2* Nicotinic Acetylcholine Receptors.
2016,
Pubmed
,
Xenbase
Jin,
The nicotinic α5 subunit can replace either an acetylcholine-binding or nonbinding subunit in the α4β2* neuronal nicotinic receptor.
2014,
Pubmed
,
Xenbase
Kowal,
Galantamine is not a positive allosteric modulator of human α4β2 or α7 nicotinic acetylcholine receptors.
2018,
Pubmed
,
Xenbase
Kuryatov,
Roles of accessory subunits in alpha4beta2(*) nicotinic receptors.
2008,
Pubmed
Kuryatov,
Acetylcholine receptor (AChR) α5 subunit variant associated with risk for nicotine dependence and lung cancer reduces (α4β2)₂α5 AChR function.
2011,
Pubmed
,
Xenbase
Li,
Functional characterization of the α5(Asn398) variant associated with risk for nicotine dependence in the α3β4α5 nicotinic receptor.
2011,
Pubmed
Lucero,
Differential α4(+)/(-)β2 Agonist-binding Site Contributions to α4β2 Nicotinic Acetylcholine Receptor Function within and between Isoforms.
2016,
Pubmed
,
Xenbase
Marotta,
Probing the non-canonical interface for agonist interaction with an α5 containing nicotinic acetylcholine receptor.
2014,
Pubmed
,
Xenbase
Mazzaferro,
Potentiation of a neuronal nicotinic receptor via pseudo-agonist site.
2019,
Pubmed
Mazzaferro,
Non-equivalent ligand selectivity of agonist sites in (α4β2)2α4 nicotinic acetylcholine receptors: a key determinant of agonist efficacy.
2014,
Pubmed
,
Xenbase
Mazzaferro,
Additional acetylcholine (ACh) binding site at alpha4/alpha4 interface of (alpha4beta2)2alpha4 nicotinic receptor influences agonist sensitivity.
2011,
Pubmed
,
Xenbase
Morales-Perez,
Manipulation of Subunit Stoichiometry in Heteromeric Membrane Proteins.
2016,
Pubmed
Morel,
Nicotine consumption is regulated by a human polymorphism in dopamine neurons.
2014,
Pubmed
Nashmi,
Assembly of alpha4beta2 nicotinic acetylcholine receptors assessed with functional fluorescently labeled subunits: effects of localization, trafficking, and nicotine-induced upregulation in clonal mammalian cells and in cultured midbrain neurons.
2003,
Pubmed
Olsen,
Structural and functional studies of the modulator NS9283 reveal agonist-like mechanism of action at α4β2 nicotinic acetylcholine receptors.
2014,
Pubmed
,
Xenbase
Ramirez-Latorre,
Functional contributions of alpha5 subunit to neuronal acetylcholine receptor channels.
1996,
Pubmed
,
Xenbase
Salas,
The nicotinic acetylcholine receptor subunit alpha 5 mediates short-term effects of nicotine in vivo.
2003,
Pubmed
Samochocki,
Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors.
2003,
Pubmed
Szabo,
Monod-Wyman-Changeux Allosteric Shift Analysis in Mutant α1β3γ2L GABAA Receptors Indicates Selectivity and Crosstalk among Intersubunit Transmembrane Anesthetic Sites.
2019,
Pubmed
,
Xenbase
Tammimäki,
Impact of human D398N single nucleotide polymorphism on intracellular calcium response mediated by α3β4α5 nicotinic acetylcholine receptors.
2012,
Pubmed
Valera,
Progesterone modulates a neuronal nicotinic acetylcholine receptor.
1992,
Pubmed
,
Xenbase
Wen,
Contribution of Variants in CHRNA5/A3/B4 Gene Cluster on Chromosome 15 to Tobacco Smoking: From Genetic Association to Mechanism.
2016,
Pubmed
Xiu,
Nicotine binding to brain receptors requires a strong cation-pi interaction.
2009,
Pubmed
,
Xenbase
Zwart,
Sazetidine-A is a potent and selective agonist at native and recombinant alpha 4 beta 2 nicotinic acetylcholine receptors.
2008,
Pubmed
,
Xenbase
