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Isoform-specific mechanisms of α3β4*-nicotinic acetylcholine receptor modulation by the prototoxin lynx1.
George AA, Bloy A, Miwa JM, Lindstrom JM, Lukas RJ, Whiteaker P.
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This study investigates-for the first time to our knowledge-the existence and mechanisms of functional interactions between the endogenous mammalian prototoxin, lynx1, and α3- and β4-subunit-containing human nicotinic acetylcholine receptors (α3β4*-nAChRs). Concatenated gene constructs were used to express precisely defined α3β4*-nAChR isoforms (α3β4)2β4-, (α3β4)2α3-, (α3β4)2α5(398D)-, and (α3β4)2α5(398N)-nAChR in Xenopus oocytes. In the presence or absence of lynx1, α3β4*-nAChR agonist responses were recorded by using 2-electrode voltage clamp and single-channel electrophysiology, whereas radioimmunolabeling measured cell-surface expression. Lynx1 reduced (α3β4)2β4-nAChR function principally by lowering cell-surface expression, whereas single-channel effects were primarily responsible for reducing (α3β4)2α3-nAChR function [decreased unitary conductance (≥50%), altered burst proportions (3-fold reduction in the proportion of long bursts), and enhanced closed dwell times (3- to 6-fold increase)]. Alterations in both cell-surface expression and single-channel properties accounted for the reduction in (α3β4)2α5-nAChR function that was mediated by lynx1. No effects were observed when α3β4*-nAChRs were coexpressed with mutated lynx1 (control). Lynx1 is expressed in the habenulopeduncular tract, where α3β4*-α5*-nAChR subtypes are critical contributors to the balance between nicotine aversion and reward. This gives our findings a high likelihood of physiologic significance. The exquisite isoform selectivity of lynx1 interactions provides new insights into the mechanisms and allosteric sites [α(-)-interface containing] by which prototoxins can modulate nAChR function.-George, A. A., Bloy, A., Miwa, J. M., Lindstrom, J. M., Lukas, R. J., Whiteaker, P. Isoform-specific mechanisms of α3β4*-nicotinic acetylcholine receptor modulation by the prototoxin lynx1.
Ahring,
Engineered α4β2 nicotinic acetylcholine receptors as models for measuring agonist binding and effect at the orthosteric low-affinity α4-α4 interface.
2015, Pubmed,
Xenbase
Ahring,
Engineered α4β2 nicotinic acetylcholine receptors as models for measuring agonist binding and effect at the orthosteric low-affinity α4-α4 interface.
2015,
Pubmed
,
Xenbase Akk,
Activation and block of mouse muscle-type nicotinic receptors by tetraethylammonium.
2003,
Pubmed Antil-Delbeke,
Molecular determinants by which a long chain toxin from snake venom interacts with the neuronal alpha 7-nicotinic acetylcholine receptor.
2000,
Pubmed Antolin-Fontes,
The habenulo-interpeduncular pathway in nicotine aversion and withdrawal.
2015,
Pubmed Auerbach,
Desensitization of mouse nicotinic acetylcholine receptor channels. A two-gate mechanism.
1998,
Pubmed Baker,
Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes.
2009,
Pubmed Barrantes,
Cell-surface translational dynamics of nicotinic acetylcholine receptors.
2014,
Pubmed Bertrand,
Activation and blocking of neuronal nicotinic acetylcholine receptor reconstituted in Xenopus oocytes.
1990,
Pubmed
,
Xenbase Bierut,
Variants in nicotinic receptors and risk for nicotine dependence.
2008,
Pubmed Boorman,
Stoichiometry of human recombinant neuronal nicotinic receptors containing the b3 subunit expressed in Xenopus oocytes.
2000,
Pubmed
,
Xenbase Boorman,
The effects of beta3 subunit incorporation on the pharmacology and single channel properties of oocyte-expressed human alpha3beta4 neuronal nicotinic receptors.
2003,
Pubmed
,
Xenbase Bourne,
Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake alpha-neurotoxins and nicotinic receptors.
2005,
Pubmed Bruneau,
Identification of nicotinic acetylcholine receptor recycling and its role in maintaining receptor density at the neuromuscular junction in vivo.
2005,
Pubmed Buisson,
Open-channel blockers at the human alpha4beta2 neuronal nicotinic acetylcholine receptor.
1998,
Pubmed Charnet,
Pharmacological and kinetic properties of alpha 4 beta 2 neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes.
1992,
Pubmed
,
Xenbase Charnet,
An open-channel blocker interacts with adjacent turns of alpha-helices in the nicotinic acetylcholine receptor.
1990,
Pubmed Chen,
Variants in nicotinic acetylcholine receptors alpha5 and alpha3 increase risks to nicotine dependence.
2009,
Pubmed Dao,
Nicotine enhances excitability of medial habenular neurons via facilitation of neurokinin signaling.
2014,
Pubmed Dellisanti,
Structural determinants for alpha-neurotoxin sensitivity in muscle nAChR and their implications for the gating mechanism.
2007,
Pubmed Dessaud,
Identification of lynx2, a novel member of the ly-6/neurotoxin superfamily, expressed in neuronal subpopulations during mouse development.
2006,
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 Fowler,
Habenular α5 nicotinic receptor subunit signalling controls nicotine intake.
2011,
Pubmed Frahm,
Aversion to nicotine is regulated by the balanced activity of β4 and α5 nicotinic receptor subunits in the medial habenula.
2011,
Pubmed
,
Xenbase Galat,
The three-fingered protein domain of the human genome.
2008,
Pubmed George,
Function of human α3β4α5 nicotinic acetylcholine receptors is reduced by the α5(D398N) variant.
2012,
Pubmed
,
Xenbase Gotti,
Structural and functional diversity of native brain neuronal nicotinic receptors.
2009,
Pubmed Grady,
Rodent habenulo-interpeduncular pathway expresses a large variety of uncommon nAChR subtypes, but only the alpha3beta4* and alpha3beta3beta4* subtypes mediate acetylcholine release.
2009,
Pubmed Grosman,
The dissociation of acetylcholine from open nicotinic receptor channels.
2001,
Pubmed Grucza,
A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence.
2008,
Pubmed Hales,
Common determinants of single channel conductance within the large cytoplasmic loop of 5-hydroxytryptamine type 3 and alpha4beta2 nicotinic acetylcholine receptors.
2006,
Pubmed Hansen,
An ion selectivity filter in the extracellular domain of Cys-loop receptors reveals determinants for ion conductance.
2008,
Pubmed Harpsøe,
Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors.
2011,
Pubmed Horie,
Isolation and characterization of a new member of the human Ly6 gene family (LY6H).
1998,
Pubmed Hruska,
Prostate stem cell antigen is an endogenous lynx1-like prototoxin that antagonizes alpha7-containing nicotinic receptors and prevents programmed cell death of parasympathetic neurons.
2009,
Pubmed Hsiao,
Zinc potentiates neuronal nicotinic receptors by increasing burst duration.
2008,
Pubmed
,
Xenbase Hurst,
Nicotinic acetylcholine receptors: from basic science to therapeutics.
2013,
Pubmed Ibañez-Tallon,
Novel modulation of neuronal nicotinic acetylcholine receptors by association with the endogenous prototoxin lynx1.
2002,
Pubmed
,
Xenbase Jackson,
Successive openings of the same acetylcholine receptor channel are correlated in open time.
1983,
Pubmed Jensen,
Prostate stem cell antigen interacts with nicotinic acetylcholine receptors and is affected in Alzheimer's disease.
2015,
Pubmed Karlin,
Emerging structure of the nicotinic acetylcholine receptors.
2002,
Pubmed Kobayashi,
Lynx1 supports neuronal health in the mouse dorsal striatum during aging: an ultrastructural investigation.
2014,
Pubmed Krashia,
Human α3β4 neuronal nicotinic receptors show different stoichiometry if they are expressed in Xenopus oocytes or mammalian HEK293 cells.
2010,
Pubmed
,
Xenbase Kumari,
Nicotinic acetylcholine receptor is internalized via a Rac-dependent, dynamin-independent endocytic pathway.
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 Li,
The neuronal nicotinic alpha4beta2 receptor has a high maximal probability of being open.
2010,
Pubmed Lucero,
Differential α4(+)/(-)β2 Agonist-binding Site Contributions to α4β2 Nicotinic Acetylcholine Receptor Function within and between Isoforms.
2016,
Pubmed
,
Xenbase Lukas,
International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits.
1999,
Pubmed Lyukmanova,
Water-soluble LYNX1 residues important for interaction with muscle-type and/or neuronal nicotinic receptors.
2013,
Pubmed Lyukmanova,
NMR structure and action on nicotinic acetylcholine receptors of water-soluble domain of human LYNX1.
2011,
Pubmed
,
Xenbase Marotta,
Probing the non-canonical interface for agonist interaction with an α5 containing nicotinic acetylcholine receptor.
2014,
Pubmed
,
Xenbase Mazzaferro,
Non-equivalent ligand selectivity of agonist sites in (α4β2)2α4 nicotinic acetylcholine receptors: a key determinant of agonist efficacy.
2014,
Pubmed
,
Xenbase McCallum,
α3β4 nicotinic acetylcholine receptors in the medial habenula modulate the mesolimbic dopaminergic response to acute nicotine in vivo.
2012,
Pubmed Militante,
Activation and block of the adult muscle-type nicotinic receptor by physostigmine: single-channel studies.
2008,
Pubmed Miwa,
The prototoxin lynx1 acts on nicotinic acetylcholine receptors to balance neuronal activity and survival in vivo.
2006,
Pubmed Miwa,
lynx1, an endogenous toxin-like modulator of nicotinic acetylcholine receptors in the mammalian CNS.
1999,
Pubmed
,
Xenbase Miwa,
Enhancement in motor learning through genetic manipulation of the Lynx1 gene.
2012,
Pubmed Miwa,
Optimizing cholinergic tone through lynx modulators of nicotinic receptors: implications for plasticity and nicotine addiction.
2012,
Pubmed Moretti,
The novel α7β2-nicotinic acetylcholine receptor subtype is expressed in mouse and human basal forebrain: biochemical and pharmacological characterization.
2014,
Pubmed
,
Xenbase Morishita,
Lynx1, a cholinergic brake, limits plasticity in adult visual cortex.
2010,
Pubmed Moroni,
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.
2008,
Pubmed
,
Xenbase Moroni,
In glycine and GABA(A) channels, different subunits contribute asymmetrically to channel conductance via residues in the extracellular domain.
2011,
Pubmed
,
Xenbase Nelson,
Single channel properties of human alpha3 AChRs: impact of beta2, beta4 and alpha5 subunits.
1999,
Pubmed
,
Xenbase Nichols,
Lynx1 shifts α4β2 nicotinic receptor subunit stoichiometry by affecting assembly in the endoplasmic reticulum.
2014,
Pubmed Nirthanan,
Candoxin, a novel toxin from Bungarus candidus, is a reversible antagonist of muscle (alphabetagammadelta ) but a poorly reversible antagonist of neuronal alpha 7 nicotinic acetylcholine receptors.
2002,
Pubmed Ochoa,
The prototoxin LYPD6B modulates heteromeric α3β4-containing nicotinic acetylcholine receptors, but not α7 homomers.
2016,
Pubmed
,
Xenbase Papke,
The role of the beta 4-subunit in determining the kinetic properties of rat neuronal nicotinic acetylcholine alpha 3-receptors.
1991,
Pubmed
,
Xenbase Premkumar,
Subconductance states of a mutant NMDA receptor channel kinetics, calcium, and voltage dependence.
1997,
Pubmed
,
Xenbase Qin,
Estimating single-channel kinetic parameters from idealized patch-clamp data containing missed events.
1996,
Pubmed
,
Xenbase Saccone,
The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans.
2009,
Pubmed Saccone,
Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs.
2007,
Pubmed Sachs,
The automated analysis of data from single ionic channels.
1982,
Pubmed Sakmann,
Patch clamp techniques for studying ionic channels in excitable membranes.
1984,
Pubmed Sakmann,
Single acetylcholine-activated channels show burst-kinetics in presence of desensitizing concentrations of agonist.
1980,
Pubmed Salas,
Nicotinic receptors in the habenulo-interpeduncular system are necessary for nicotine withdrawal in mice.
2009,
Pubmed Shahsavar,
Acetylcholine-Binding Protein Engineered to Mimic the α4-α4 Binding Pocket in α4β2 Nicotinic Acetylcholine Receptors Reveals Interface Specific Interactions Important for Binding and Activity.
2015,
Pubmed
,
Xenbase Sheffield,
Nicotinic acetylcholine receptor subunit mRNA expression and channel function in medial habenula neurons.
2000,
Pubmed
,
Xenbase Shih,
Differential expression and function of nicotinic acetylcholine receptors in subdivisions of medial habenula.
2014,
Pubmed Shulepko,
Human neuromodulator SLURP-1: bacterial expression, binding to muscle-type nicotinic acetylcholine receptor, secondary structure, and conformational heterogeneity in solution.
2013,
Pubmed Sine,
Activation of a nicotinic acetylcholine receptor.
1984,
Pubmed Sivilotti,
Recombinant nicotinic receptors, expressed in Xenopus oocytes, do not resemble native rat sympathetic ganglion receptors in single-channel behaviour.
1997,
Pubmed
,
Xenbase Slimak,
Habenular expression of rare missense variants of the β4 nicotinic receptor subunit alters nicotine consumption.
2014,
Pubmed Srinivasan,
Nicotine up-regulates alpha4beta2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning.
2011,
Pubmed Stevens,
Nicotinic receptor gene variants influence susceptibility to heavy smoking.
2008,
Pubmed St John,
Cellular trafficking of nicotinic acetylcholine receptors.
2009,
Pubmed Wang,
An Accessory Agonist Binding Site Promotes Activation of α4β2* Nicotinic Acetylcholine Receptors.
2015,
Pubmed
,
Xenbase Whiteaker,
Involvement of the alpha3 subunit in central nicotinic binding populations.
2002,
Pubmed Whiteaker,
125I-alpha-conotoxin MII identifies a novel nicotinic acetylcholine receptor population in mouse brain.
2000,
Pubmed Whiting,
Purification and characterization of a nicotinic acetylcholine receptor from chick brain.
1986,
Pubmed Wu,
Naturally-expressed nicotinic acetylcholine receptor subtypes.
2011,
Pubmed Wu,
Structural Analysis and Deletion Mutagenesis Define Regions of QUIVER/SLEEPLESS that Are Responsible for Interactions with Shaker-Type Potassium Channels and Nicotinic Acetylcholine Receptors.
2016,
Pubmed Wu,
Mechanisms of inhibition and potentiation of α4β2 nicotinic acetylcholine receptors by members of the Ly6 protein family.
2015,
Pubmed Zhang,
Identification and characterization of human LYPD6, a new member of the Ly-6 superfamily.
2010,
Pubmed Zhou,
Human alpha4beta2 acetylcholine receptors formed from linked subunits.
2003,
Pubmed
,
Xenbase
