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Mol Pharmacol
2010 Aug 01;782:198-204. doi: 10.1124/mol.110.064295.
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Nicotinic acetylcholine receptor transmembrane mutations convert ivermectin from a positive to a negative allosteric modulator.
Collins T
,
Millar NS
.
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Ivermectin is a macrocyclic lactone that acts as a positive allosteric modulator of alpha7 nicotinic acetylcholine receptors (nAChRs) but has no modulatory activity on 5-hydroxytryptamine (5-HT) type 3 (5-HT(3)) receptors. By examining the influence of ivermectin on subunit chimeras containing domains from the nAChR alpha7 subunit and the 5-HT3A subunit, we have concluded that the transmembrane domains play a critical role in influencing allosteric modulation by ivermectin. A series of mutations located within the alpha-helical transmembrane domains of the alpha7 subunit were examined, and seven were found to have significant effects on allosteric modulation by ivermectin. Four mutations (A225D, Q272V, T456Y, and C459Y) caused a significant reduction in the potency of ivermectin as an allosteric potentiator. Compared with wild-type alpha7 nAChRs, potentiation by ivermectin was reduced dramatically (by 89-97%) by these mutations. Somewhat unexpectedly, three mutations (S222M, M253L, and S276V located in TM1, TM2, and TM3) converted ivermectin from a positive allosteric modulator into an antagonist. Levels of inhibition of 56, 84, and 89% were observed on M253L, S276V, and S222M, respectively. Antagonism by ivermectin was insurmountable and had no effect on EC(50) of acetylcholine, indicating that it is acting noncompetitively. The seven mutations that influence allosteric modulation by ivermectin are located near a predicted intrasubunit transmembrane cavity. Computer docking simulations provide support for the hypothesis that ivermectin binds in close proximity to this cavity. We conclude that transmembrane mutations in alpha7 nAChRs are able to convert ivermectin from a positive to a negative allosteric modulator.
Adelsberger,
Activation of rat recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptor by the insecticide ivermectin.
2000, Pubmed
Adelsberger,
Activation of rat recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptor by the insecticide ivermectin.
2000,
Pubmed
Arena,
The mechanism of action of avermectins in Caenorhabditis elegans: correlation between activation of glutamate-sensitive chloride current, membrane binding, and biological activity.
1995,
Pubmed
,
Xenbase
Bertrand,
Positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor: ligand interactions with distinct binding sites and evidence for a prominent role of the M2-M3 segment.
2008,
Pubmed
,
Xenbase
Bertrand,
Allosteric modulation of nicotinic acetylcholine receptors.
2007,
Pubmed
Broad,
Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators.
2006,
Pubmed
,
Xenbase
Burkhart,
Ivermectin: an assessment of its pharmacology, microbiology and safety.
2000,
Pubmed
Cheng,
Channel opening motion of alpha7 nicotinic acetylcholine receptor as suggested by normal mode analysis.
2006,
Pubmed
Chimienti,
Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda.
2003,
Pubmed
,
Xenbase
Conroy,
Potentiation of alpha7-containing nicotinic acetylcholine receptors by select albumins.
2003,
Pubmed
Cooper,
Host cell-specific folding of the neuronal nicotinic receptor alpha8 subunit.
1998,
Pubmed
,
Xenbase
Gee,
Identification of domains influencing assembly and ion channel properties in alpha 7 nicotinic receptor and 5-HT3 receptor subunit chimaeras.
2007,
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
Hosie,
Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites.
2006,
Pubmed
Hurst,
A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization.
2005,
Pubmed
,
Xenbase
Hussy,
Agonist and antagonist effects of nicotine on chick neuronal nicotinic receptors are defined by alpha and beta subunits.
1994,
Pubmed
,
Xenbase
Jelínkova,
Identification of P2X(4) receptor transmembrane residues contributing to channel gating and interaction with ivermectin.
2008,
Pubmed
Khakh,
Allosteric control of gating and kinetics at P2X(4) receptor channels.
1999,
Pubmed
,
Xenbase
Krause,
Ivermectin: a positive allosteric effector of the alpha7 neuronal nicotinic acetylcholine receptor.
1998,
Pubmed
,
Xenbase
Krůsek,
Effect of ivermectin on gamma-aminobutyric acid-induced chloride currents in mouse hippocampal embryonic neurones.
1994,
Pubmed
Lansdell,
RIC-3 enhances functional expression of multiple nicotinic acetylcholine receptor subtypes in mammalian cells.
2005,
Pubmed
,
Xenbase
Lobo,
Accessibility to residues in transmembrane segment four of the glycine receptor.
2006,
Pubmed
Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase
Millar,
RIC-3: a nicotinic acetylcholine receptor chaperone.
2008,
Pubmed
Miyazawa,
Structure and gating mechanism of the acetylcholine receptor pore.
2003,
Pubmed
Moaddel,
Allosteric modifiers of neuronal nicotinic acetylcholine receptors: new methods, new opportunities.
2007,
Pubmed
Raymond,
Novel animal-health drug targets from ligand-gated chloride channels.
2002,
Pubmed
Raymond,
Anthelmintic actions on homomer-forming nicotinic acetylcholine receptor subunits: chicken alpha7 and ACR-16 from the nematode Caenorhabditis elegans.
2000,
Pubmed
,
Xenbase
Samochocki,
Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors.
2003,
Pubmed
Sattelle,
Comparative pharmacology and computational modelling yield insights into allosteric modulation of human alpha7 nicotinic acetylcholine receptors.
2009,
Pubmed
,
Xenbase
Shan,
Ivermectin, an unconventional agonist of the glycine receptor chloride channel.
2001,
Pubmed
Sigel,
Effect of avermectin B1a on chick neuronal gamma-aminobutyrate receptor channels expressed in Xenopus oocytes.
1987,
Pubmed
,
Xenbase
Silberberg,
Ivermectin Interaction with transmembrane helices reveals widespread rearrangements during opening of P2X receptor channels.
2007,
Pubmed
,
Xenbase
Timmermann,
An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo.
2007,
Pubmed
,
Xenbase
Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed
Ye,
Enhancement of glycine receptor function by ethanol is inversely correlated with molecular volume at position alpha267.
1998,
Pubmed
,
Xenbase
Young,
Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site.
2008,
Pubmed
,
Xenbase
Young,
Species selectivity of a nicotinic acetylcholine receptor agonist is conferred by two adjacent extracellular beta4 amino acids that are implicated in the coupling of binding to channel gating.
2007,
Pubmed
Zheng,
Identification of two novel Drosophila melanogaster histamine-gated chloride channel subunits expressed in the eye.
2002,
Pubmed
Zwart,
5-Hydroxyindole potentiates human alpha 7 nicotinic receptor-mediated responses and enhances acetylcholine-induced glutamate release in cerebellar slices.
2002,
Pubmed
,
Xenbase
