Selectivity of (±)-citalopram at nicotinic acetylcholine receptors and different inhibitory mechanisms between habenular α3β4* and α9α10 subtypes

Hugo R. Arias; Xiao Tao Jin; Sofía Gallino; Can Peng; Dominik Feuerbach; Jesús García-Colunga; Ana Belén Elgoyhen; Ryan M. Drenan; Marcelo O. Ortells

doi:10.1016/j.neuint.2019.104552

Selectivity of (±)-citalopram at nicotinic acetylcholine receptors and different inhibitory mechanisms between habenular α3β4* and α9α10 subtypes

Hugo R. Arias, Xiao Tao Jin, Sofía Gallino, Can Peng, Dominik Feuerbach, Jesús García-Colunga, Ana Belén Elgoyhen, Ryan M. Drenan, Marcelo O. Ortells^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

The inhibitory activity of (±)-citalopram on human (h) α3β4, α4β2, and α7 nicotinic acetylcholine receptors (AChRs) was determined by Ca²⁺ influx assays, whereas its effect on rat α9α10 and mouse habenular α3β4* AChRs by electrophysiological recordings. The Ca²⁺ influx results clearly establish that (±)-citalopram inhibits (IC₅₀'s in μM) hα3β4 AChRs (5.1 ± 1.3) with higher potency than that for hα7 (18.8 ± 1.1) and hα4β2 (19.1 ± 4.2) AChRs. This is in agreement with the [³H]imipramine competition binding results indicating that (±)-citalopram binds to imipramine sites at desensitized hα3β4 with >2-fold higher affinity than that for hα4β2. The electrophysiological, molecular docking, and in silico mutation results indicate that (±)-citalopram competitively inhibits rα9α10 AChRs (7.5 ± 0.9) in a voltage-independent manner by interacting mainly with orthosteric sites, whereas it inhibits a homogeneous population of α3β4* AChRs at MHb (VI) neurons (7.6 ± 1.0) in a voltage-dependent manner by interacting mainly with a luminal site located in the middle of the ion channel, overlapping the imipramine site, which suggests an ion channel blocking mechanism. In conclusion, (±)-citalopram inhibits α3β4 and α9α10 AChRs with higher potency compared to other AChRs but by different mechanisms. (±)-Citalopram also inhibits habenular α3β4*AChRs, supporting the notion that these receptors are important endogenous targets related to their anti-addictive activities.

Original language	English (US)
Article number	104552
Journal	Neurochemistry International
Volume	131
DOIs	https://doi.org/10.1016/j.neuint.2019.104552
State	Published - Dec 2019

Funding

This work was supported by grants from NIH ( DA040626 ) (to R.M.D.), National Agency for Scientific and Technologic Promotion, Argentina (to A.B.E.), and Dirección General de Asuntos del Personal Académico, UNAM, Mexico (PASPA grant) (to J.G-C) and Oklahoma State University (to H.R.A.). This work was supported by grants from NIH (DA040626) (to R.M.D.), National Agency for Scientific and Technologic Promotion, Argentina (to A.B.E.), and Direcci?n General de Asuntos del Personal Acad?mico, UNAM, Mexico (PASPA grant) (to J.G-C) and Oklahoma State University (to H.R.A.).

Keywords

(±)-Citalopram
Brain slices
Medial habenula
Nicotinic acetylcholine receptor
Selective serotonin reuptake inhibitor

ASJC Scopus subject areas

Cellular and Molecular Neuroscience
Cell Biology

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10.1016/j.neuint.2019.104552

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Arias, H. R., Jin, X. T., Gallino, S., Peng, C., Feuerbach, D., García-Colunga, J., Elgoyhen, A. B., Drenan, R. M., & Ortells, M. O. (2019). Selectivity of (±)-citalopram at nicotinic acetylcholine receptors and different inhibitory mechanisms between habenular α3β4* and α9α10 subtypes. Neurochemistry International, 131, Article 104552. https://doi.org/10.1016/j.neuint.2019.104552

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title = "Selectivity of (±)-citalopram at nicotinic acetylcholine receptors and different inhibitory mechanisms between habenular α3β4* and α9α10 subtypes",

abstract = "The inhibitory activity of (±)-citalopram on human (h) α3β4, α4β2, and α7 nicotinic acetylcholine receptors (AChRs) was determined by Ca2+ influx assays, whereas its effect on rat α9α10 and mouse habenular α3β4* AChRs by electrophysiological recordings. The Ca2+ influx results clearly establish that (±)-citalopram inhibits (IC50's in μM) hα3β4 AChRs (5.1 ± 1.3) with higher potency than that for hα7 (18.8 ± 1.1) and hα4β2 (19.1 ± 4.2) AChRs. This is in agreement with the [3H]imipramine competition binding results indicating that (±)-citalopram binds to imipramine sites at desensitized hα3β4 with >2-fold higher affinity than that for hα4β2. The electrophysiological, molecular docking, and in silico mutation results indicate that (±)-citalopram competitively inhibits rα9α10 AChRs (7.5 ± 0.9) in a voltage-independent manner by interacting mainly with orthosteric sites, whereas it inhibits a homogeneous population of α3β4* AChRs at MHb (VI) neurons (7.6 ± 1.0) in a voltage-dependent manner by interacting mainly with a luminal site located in the middle of the ion channel, overlapping the imipramine site, which suggests an ion channel blocking mechanism. In conclusion, (±)-citalopram inhibits α3β4 and α9α10 AChRs with higher potency compared to other AChRs but by different mechanisms. (±)-Citalopram also inhibits habenular α3β4*AChRs, supporting the notion that these receptors are important endogenous targets related to their anti-addictive activities.",

keywords = "(±)-Citalopram, Brain slices, Medial habenula, Nicotinic acetylcholine receptor, Selective serotonin reuptake inhibitor",

author = "Arias, {Hugo R.} and Jin, {Xiao Tao} and Sof{\'i}a Gallino and Can Peng and Dominik Feuerbach and Jes{\'u}s Garc{\'i}a-Colunga and Elgoyhen, {Ana Bel{\'e}n} and Drenan, {Ryan M.} and Ortells, {Marcelo O.}",

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doi = "10.1016/j.neuint.2019.104552",

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AU - Arias, Hugo R.

AU - Jin, Xiao Tao

AU - Gallino, Sofía

AU - Peng, Can

AU - Feuerbach, Dominik

AU - García-Colunga, Jesús

AU - Elgoyhen, Ana Belén

AU - Drenan, Ryan M.

AU - Ortells, Marcelo O.

PY - 2019/12

Y1 - 2019/12

N2 - The inhibitory activity of (±)-citalopram on human (h) α3β4, α4β2, and α7 nicotinic acetylcholine receptors (AChRs) was determined by Ca2+ influx assays, whereas its effect on rat α9α10 and mouse habenular α3β4* AChRs by electrophysiological recordings. The Ca2+ influx results clearly establish that (±)-citalopram inhibits (IC50's in μM) hα3β4 AChRs (5.1 ± 1.3) with higher potency than that for hα7 (18.8 ± 1.1) and hα4β2 (19.1 ± 4.2) AChRs. This is in agreement with the [3H]imipramine competition binding results indicating that (±)-citalopram binds to imipramine sites at desensitized hα3β4 with >2-fold higher affinity than that for hα4β2. The electrophysiological, molecular docking, and in silico mutation results indicate that (±)-citalopram competitively inhibits rα9α10 AChRs (7.5 ± 0.9) in a voltage-independent manner by interacting mainly with orthosteric sites, whereas it inhibits a homogeneous population of α3β4* AChRs at MHb (VI) neurons (7.6 ± 1.0) in a voltage-dependent manner by interacting mainly with a luminal site located in the middle of the ion channel, overlapping the imipramine site, which suggests an ion channel blocking mechanism. In conclusion, (±)-citalopram inhibits α3β4 and α9α10 AChRs with higher potency compared to other AChRs but by different mechanisms. (±)-Citalopram also inhibits habenular α3β4*AChRs, supporting the notion that these receptors are important endogenous targets related to their anti-addictive activities.

AB - The inhibitory activity of (±)-citalopram on human (h) α3β4, α4β2, and α7 nicotinic acetylcholine receptors (AChRs) was determined by Ca2+ influx assays, whereas its effect on rat α9α10 and mouse habenular α3β4* AChRs by electrophysiological recordings. The Ca2+ influx results clearly establish that (±)-citalopram inhibits (IC50's in μM) hα3β4 AChRs (5.1 ± 1.3) with higher potency than that for hα7 (18.8 ± 1.1) and hα4β2 (19.1 ± 4.2) AChRs. This is in agreement with the [3H]imipramine competition binding results indicating that (±)-citalopram binds to imipramine sites at desensitized hα3β4 with >2-fold higher affinity than that for hα4β2. The electrophysiological, molecular docking, and in silico mutation results indicate that (±)-citalopram competitively inhibits rα9α10 AChRs (7.5 ± 0.9) in a voltage-independent manner by interacting mainly with orthosteric sites, whereas it inhibits a homogeneous population of α3β4* AChRs at MHb (VI) neurons (7.6 ± 1.0) in a voltage-dependent manner by interacting mainly with a luminal site located in the middle of the ion channel, overlapping the imipramine site, which suggests an ion channel blocking mechanism. In conclusion, (±)-citalopram inhibits α3β4 and α9α10 AChRs with higher potency compared to other AChRs but by different mechanisms. (±)-Citalopram also inhibits habenular α3β4*AChRs, supporting the notion that these receptors are important endogenous targets related to their anti-addictive activities.

KW - (±)-Citalopram

KW - Brain slices

KW - Medial habenula

KW - Nicotinic acetylcholine receptor

KW - Selective serotonin reuptake inhibitor

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Selectivity of (±)-citalopram at nicotinic acetylcholine receptors and different inhibitory mechanisms between habenular α3β4* and α9α10 subtypes

Abstract

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