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

Research output: Contribution to journalArticle

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 languageEnglish
Article number104552
JournalNeurochemistry International
Volume131
DOIs
StatePublished - 1 Dec 2019

Fingerprint

Citalopram
Nicotinic Receptors
Cholinergic Receptors
Imipramine
Ion Channels
Computer Simulation
Inhibitory Concentration 50
Neurons
Mutation

Keywords

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

Cite this

Arias, Hugo R. ; Jin, Xiao Tao ; Gallino, Sofía ; Peng, Can ; Feuerbach, Dominik ; García-Colunga, Jesús ; Elgoyhen, Ana Belén ; Drenan, Ryan M. ; Ortells, Marcelo O. / Selectivity of (±)-citalopram at nicotinic acetylcholine receptors and different inhibitory mechanisms between habenular α3β4* and α9α10 subtypes. In: Neurochemistry International. 2019 ; Vol. 131.
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Selectivity of (±)-citalopram at nicotinic acetylcholine receptors and different inhibitory mechanisms between habenular α3β4* and α9α10 subtypes. / Arias, Hugo R.; Jin, Xiao Tao; Gallino, Sofía; Peng, Can; Feuerbach, Dominik; García-Colunga, Jesús; Elgoyhen, Ana Belén; Drenan, Ryan M.; Ortells, Marcelo O.

In: Neurochemistry International, Vol. 131, 104552, 01.12.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Selectivity of (±)-citalopram at nicotinic acetylcholine receptors and different inhibitory mechanisms between habenular α3β4* and α9α10 subtypes

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.

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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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