ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2008
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.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed.
- Structural basis of human zinc-activated channel (ZAC) signaling and modulation.Cell discovery · 2026Article
- Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators.Molecules (Basel, Switzerland) · 2023Review
- Stoichiometry-Selective Antagonism of α4β2 Nicotinic Acetylcholine Receptors by Fluoroquinolone Antibiotics.ACS chemical neuroscience · 2022Article
- Stoichiometry-selective modulation of α4β2 nicotinic ACh receptors by divalent cations.British journal of pharmacology · 2022Article
- Probing the molecular basis for signal transduction through the Zinc-Activated Channel (ZAC).Biochemical pharmacology · 2021Article
- Zinc and Copper Brain Levels and Expression of Neurotransmitter Receptors in Two Rat ASD Models.Frontiers in molecular neuroscience · 2021Article
- Potentiation of a neuronal nicotinic receptor via pseudo-agonist site.Cellular and molecular life sciences : CMLS · 2019Article
- Molecular function of the novel α7β2 nicotinic receptor.Cellular and molecular life sciences : CMLS · 2018Article
- The fifth subunit of the (α4β2)British journal of pharmacology · 2018Article
- Stoichiometry of the Heteromeric Nicotinic Receptors of the Renshaw Cell.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Methylpiperidinium Iodides as Novel Antagonists for α7 Nicotinic Acetylcholine Receptors.Frontiers in pharmacology · 2018Article
- Isoform-specific mechanisms of α3β4*-nicotinic acetylcholine receptor modulation by the prototoxin lynx1.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- α4β2 Nicotinic Acetylcholine Receptors: RELATIONSHIPS BETWEEN SUBUNIT STOICHIOMETRY AND FUNCTION AT THE SINGLE CHANNEL LEVEL.The Journal of biological chemistry · 2017Article
- The E Loop of the Transmitter Binding Site Is a Key Determinant of the Modulatory Effects of Physostigmine on Neuronal Nicotinic α4β2 Receptors.Molecular pharmacology · 2017Article
- Role of the Cys Loop and Transmembrane Domain in the Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors.The Journal of biological chemistry · 2017Article
- Crystal structure of a human neuronal nAChR extracellular domain in pentameric assembly: Ligand-bound α2 homopentamer.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- The prototoxin LYPD6B modulates heteromeric α3β4-containing nicotinic acetylcholine receptors, but not α7 homomers.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2016Article
- Differential α4(+)/(-)β2 Agonist-binding Site Contributions to α4β2 Nicotinic Acetylcholine Receptor Function within and between Isoforms.The Journal of biological chemistry · 2016Article
- Article
- Desformylflustrabromine Modulates α4β2 Neuronal Nicotinic Acetylcholine Receptor High- and Low-Sensitivity Isoforms at Allosteric Clefts Containing the β2 Subunit.The Journal of pharmacology and experimental therapeutics · 2015Article
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Authors and funding
6 authors.
Funding
Abstract
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.
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