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Non-agonist-binding subunit interfaces confer distinct functional signatures to the alternate stoichiometries of the alpha4beta2 nicotinic receptor: an alpha4-alpha4 interface is required for Zn2+ potentiation.
Moroni M
,
Vijayan R
,
Carbone A
,
Zwart R
,
Biggin PC
,
Bermudez I
.
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The alpha4beta2 subtype is the most abundant nicotinic acetylcholine receptor (nAChR) in the brain and possesses the high-affinity binding site for nicotine. The alpha4 and beta2 nAChR subunits assemble into two alternate stoichiometries, (alpha4)(2)(beta2)(3) and (alpha4)(3)(beta2)(2), which differ in their functional properties and sensitivity to chronic exposure to nicotine. Here, we investigated the sensitivity of both receptor stoichiometries to modulation by Zn2+. We show that Zn2+ exerts an inhibitory modulatory effect on (alpha4)(2)(beta2)(3) receptors, whereas it potentiates or inhibits, depending on its concentration, the function of (alpha4)(3)(beta2)(2) receptors. Furthermore, Zn2+ inhibition on (alpha4)(2)(beta2)(3) nAChRs is voltage-dependent, whereas it is not on (alpha4)(3)(beta2)(2) receptors. We used molecular modeling in conjunction with alanine substitution and functional studies to identify two distinct sets of residues that determine these effects and may coordinate Zn(2+). Zn(2+) inhibition is mediated by a site located on the beta2(+)/alpha4(-) subunit interfaces on both receptor stoichiometries. alpha4(H195) and beta2(D218) are key determinants of this site. Zn2+ potentiation on (alpha4)(3)(beta2)(2) nAChRs is exerted by a site that resides on the alpha4(+)/alpha4(-) of this receptor stoichiometry. alpha4(H195) on the (-) side of the ACh-binding alpha4 subunit and alpha4(E224) on the (+) side of the non-ACh-binding alpha4 subunit critically contribute to this site. We also identified residues within the beta2 subunit that confer voltage dependency to Zn2+ inhibition on (alpha4)(2)(beta2)(3), but not on (alpha4)(3)(beta2)(2) nAChRs.
Auld,
Zinc coordination sphere in biochemical zinc sites.
2001, Pubmed
Auld,
Zinc coordination sphere in biochemical zinc sites.
2001,
Pubmed
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Briggs,
Untranslated region-dependent exclusive expression of high-sensitivity subforms of alpha4beta2 and alpha3beta2 nicotinic acetylcholine receptors.
2006,
Pubmed
,
Xenbase
Butt,
Bovine serum albumin enhances nicotinic acetylcholine receptor function in mouse thalamic synaptosomes.
2002,
Pubmed
Castagnetto,
MDB: the Metalloprotein Database and Browser at The Scripps Research Institute.
2002,
Pubmed
Celie,
Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures.
2004,
Pubmed
Choi,
Identification and mechanism of action of two histidine residues underlying high-affinity Zn2+ inhibition of the NMDA receptor.
1999,
Pubmed
,
Xenbase
Dunne,
An N-terminal histidine regulates Zn(2+) inhibition on the murine GABA(A) receptor beta3 subunit.
2002,
Pubmed
,
Xenbase
Exley,
Chaperone protein 14-3-3 and protein kinase A increase the relative abundance of low agonist sensitivity human alpha 4 beta 2 nicotinic acetylcholine receptors in Xenopus oocytes.
2006,
Pubmed
,
Xenbase
García-Colunga,
Modulation of alpha2beta4 neuronal nicotinic acetylcholine receptors by zinc.
2001,
Pubmed
,
Xenbase
Gasteiger,
ExPASy: The proteomics server for in-depth protein knowledge and analysis.
2003,
Pubmed
Hansen,
Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations.
2005,
Pubmed
Hansen,
Galanthamine and non-competitive inhibitor binding to ACh-binding protein: evidence for a binding site on non-alpha-subunit interfaces of heteromeric neuronal nicotinic receptors.
2007,
Pubmed
Henchman,
Asymmetric structural motions of the homomeric alpha7 nicotinic receptor ligand binding domain revealed by molecular dynamics simulation.
2003,
Pubmed
Henchman,
Ligand-induced conformational change in the alpha7 nicotinic receptor ligand binding domain.
2005,
Pubmed
Hosie,
Zinc-mediated inhibition of GABA(A) receptors: discrete binding sites underlie subtype specificity.
2003,
Pubmed
Houlihan,
Activity of cytisine and its brominated isosteres on recombinant human alpha7, alpha4beta2 and alpha4beta4 nicotinic acetylcholine receptors.
2001,
Pubmed
,
Xenbase
Hsiao,
Subunit-dependent modulation of neuronal nicotinic receptors by zinc.
2001,
Pubmed
,
Xenbase
Hsiao,
Determinants of zinc potentiation on the alpha4 subunit of neuronal nicotinic receptors.
2006,
Pubmed
,
Xenbase
Kim,
The mouse Chrna4 A529T polymorphism alters the ratio of high to low affinity alpha 4 beta 2 nAChRs.
2003,
Pubmed
Kuryatov,
Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors.
2005,
Pubmed
Low,
Molecular determinants of coordinated proton and zinc inhibition of N-methyl-D-aspartate NR1/NR2A receptors.
2000,
Pubmed
,
Xenbase
McCall,
Function and mechanism of zinc metalloenzymes.
2000,
Pubmed
Miles,
Modification of histidyl residues in proteins by diethylpyrocarbonate.
1977,
Pubmed
Miller,
Molecular determinants of glycine receptor alphabeta subunit sensitivities to Zn2+-mediated inhibition.
2005,
Pubmed
Miller,
Molecular basis for zinc potentiation at strychnine-sensitive glycine receptors.
2005,
Pubmed
Moroni,
alpha4beta2 nicotinic receptors with high and low acetylcholine sensitivity: pharmacology, stoichiometry, and sensitivity to long-term exposure to nicotine.
2006,
Pubmed
,
Xenbase
Nagaya,
An intersubunit zinc binding site in rat P2X2 receptors.
2005,
Pubmed
,
Xenbase
Nelson,
Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Nutter,
Monovalent and divalent cation permeability and block of neuronal nicotinic receptor channels in rat parasympathetic ganglia.
1995,
Pubmed
Paoletti,
High-affinity zinc inhibition of NMDA NR1-NR2A receptors.
1997,
Pubmed
,
Xenbase
Picciotto,
Neuronal nicotinic acetylcholine receptor subunit knockout mice: physiological and behavioral phenotypes and possible clinical implications.
2001,
Pubmed
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Sigel,
The benzodiazepine binding site of GABAA receptors.
1997,
Pubmed
Szarecka,
Dynamics of heteropentameric nicotinic acetylcholine receptor: implications of the gating mechanism.
2007,
Pubmed
Tapia,
Ca2+ permeability of the (alpha4)3(beta2)2 stoichiometry greatly exceeds that of (alpha4)2(beta2)3 human acetylcholine receptors.
2007,
Pubmed
,
Xenbase
Thompson,
CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice.
1994,
Pubmed
Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed
Zwart,
Four pharmacologically distinct subtypes of alpha4beta2 nicotinic acetylcholine receptor expressed in Xenopus laevis oocytes.
1998,
Pubmed
,
Xenbase
Zwart,
5-I A-85380 and TC-2559 differentially activate heterologously expressed alpha4beta2 nicotinic receptors.
2006,
Pubmed
,
Xenbase
