Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

Sattelle, David B.; Akamatsu, Miki; Matsuda, Kazuhiko; Pienaar, Ilse S.; Jones, Andrew K.; Sattelle, Benedict M.; Almond, Andrew; Blundell, Charles

doi:10.1016/j.bcp.2009.06.020

Cited by 38 publications

(43 citation statements)

References 55 publications

(74 reference statements)

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“…In the Caenorhabditis elegans GluCl crystal structure, ivermectin contacts both the TM2-3 linker and the residues toward the middle of the TMD (18). Mutational analysis on ␣7nAChR also suggests that ivermectin interacts with residues near the TM2-3 linker and residues near the middle of the TMD (16,59). If direct contacts to specific residues in the TM2-3 linker are critical for ivermectin modulation, the ELIC TM2-3 linker may not provide proper contacts in EA ELIC and EA ELIC 5 , thereby preventing ivermectin modulation.…”

Section: Discussionmentioning

confidence: 99%

ELIC-α7 Nicotinic Acetylcholine Receptor (α7nAChR) Chimeras Reveal a Prominent Role of the Extracellular-Transmembrane Domain Interface in Allosteric Modulation

Tillman¹,

Seyoum²,

Mowrey

et al. 2014

Journal of Biological Chemistry

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Background: Allosteric modulators bound to the transmembrane domain (TMD) of the ␣7 nicotinic acetylcholine receptor (␣7nAChR) can potentiate channel function. Results: ELIC-␣7nAChR showed potentiation only when the extracellular-transmembrane domain (ECD-TMD) interface matched that of ␣7nAChR. Conclusion: PAM modulation through the TMD requires a more specific ECD-TMD interface than agonist activation. Significance: The study provides insight into the basis for positive allosteric modulation of ␣7nAChR.

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Section: Discussionmentioning

confidence: 99%

ELIC-α7 Nicotinic Acetylcholine Receptor (α7nAChR) Chimeras Reveal a Prominent Role of the Extracellular-Transmembrane Domain Interface in Allosteric Modulation

Tillman¹,

Seyoum²,

Mowrey

et al. 2014

Journal of Biological Chemistry

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“…We started with the long axis of the IVM molecule essentially parallel to and in proximity of the extracellular membrane surface, as in GluCl [32]. We, then, compared the position of IVM in this model with the orientation of IVM in the alpha-helical bundle described previously [37]. In that model the spiroketal and benzofuran rings are near Trp46 and Trp50 while the disaccharide is pointing along the long axis of the alpha helices.…”

Section: Molecular Model Of P2x4rs Focused On Position 46 Interactionmentioning

confidence: 99%

Tryptophan 46 is a site for ethanol and ivermectin action in P2X4 receptors

Popova

Trudell

et al. 2013

Purinergic Signalling

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ATP-gated purinergic P2X4 receptors (P2X4Rs) are the most alcohol-sensitive P2XR subtype. We recently reported that ivermectin (IVM), an antiparasitic used in animals and humans, antagonized ethanol inhibition of P2X4Rs. Furthermore, IVM reduced ethanol intake in mice. The first molecular model of the rat P2X4R, built onto the Xray crystal structure of zebrafish P2X4R, revealed an action pocket for both ethanol and IVM formed by Asp331, Met336 in TM2 and Trp46, and Trp50 in TM1 segments. The role of Asp331 and Met336 was experimentally confirmed. The present study tested the hypothesis that Trp46 plays a role in ethanol and IVM modulation of P2X4Rs. Trp46 was mutated to residues with different physicochemical properties and the resultant mutants tested for ethanol and IVM responses using Xenopus oocyte expression system and twoelectrode voltage clamp. Nonaromatic substitutions at position 46 reduced ethanol inhibition at higher concentrations and switched IVM potentiation to inhibition. Simultaneous substitution of alanine at positions Trp46 and Met336 also resulted in similar changes in ethanol and IVM responses. Furthermore, a new molecular model based on the open pore conformation of zebrafish P2X4R suggested a role for Tyr42 that was further supported experimentally. Our previous and current findings, combined with our preliminary evidence of increased ethanol consumption in P2X4R knockout mice, suggest that the ethanol and IVM action pocket in P2X4Rs formed by positions 42, 46, 331, and 336 presents a potential target for medication development for alcohol use disorders.

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“…In contrast, for allosteric potentiators such as LY-2087101 and PNU-120596, a transmembrane binding site has been proposed (Young et al, 2008). It has been suggested, on the strength of computer docking simulations, that ivermectin may also interact with nAChRs via a transmembrane binding site (Sattelle et al, 2009). In the present study, we examined the ability of ivermectin to act as an allosteric modulator on a series of mutated and chimeric ␣7 nAChR subunits.…”

mentioning

confidence: 93%

Nicotinic Acetylcholine Receptor Transmembrane Mutations Convert Ivermectin from a Positive to a Negative Allosteric Modulator

Collins

Millar

2010

Mol Pharmacol

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Ivermectin is a macrocyclic lactone that acts as a positive allosteric modulator of ␣7 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 ␣7 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 ␣-helical transmembrane domains of the ␣7 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 ␣7 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 ␣7 nAChRs are able to convert ivermectin from a positive to a negative allosteric modulator.

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Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

Cited by 38 publications

References 55 publications

ELIC-α7 Nicotinic Acetylcholine Receptor (α7nAChR) Chimeras Reveal a Prominent Role of the Extracellular-Transmembrane Domain Interface in Allosteric Modulation

ELIC-α7 Nicotinic Acetylcholine Receptor (α7nAChR) Chimeras Reveal a Prominent Role of the Extracellular-Transmembrane Domain Interface in Allosteric Modulation

Tryptophan 46 is a site for ethanol and ivermectin action in P2X4 receptors

Nicotinic Acetylcholine Receptor Transmembrane Mutations Convert Ivermectin from a Positive to a Negative Allosteric Modulator

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