Different Classes of Antidepressants Inhibit the Rat α7 Nicotinic Acetylcholine Receptor by Interacting within the Ion Channel: A Functional and Structural Study.

Yorley Duarte,Jonathan Canan,Maximiliano Rojas,Jesús García-Colunga,Edwin G Pérez,Fernando González-Nilo

doi:10.3390/molecules26040998

Abstract

Several antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a non-competitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological profile modulate the rat α7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording of the ion current elicited by choline, ICh, which activates α7 nAChRs from rat CA1 hippocampal interneurons) and in silico approaches (homology modeling of the rat α7 nAChR, molecular docking, molecular dynamics simulations, and binding free energy calculations). The antidepressants inhibited ICh with the order: norfluoxetine ~ mirtazapine ~ imipramine < bupropion ~ fluoxetine ~ venlafaxine ~ escitalopram. The constructed homology model of the rat α7 nAChR resulted in the extracellular vestibule and the channel pore is highly negatively charged, which facilitates the permeation of cations and the entrance of the protonated form of antidepressants. Molecular docking and molecular dynamics simulations were carried out within the ion−channel of the α7 nAChR, revealing that the antidepressants adopt poses along the receptor channel, with slightly different binding-free energy values. Furthermore, the inhibition of ICh and free energy values for each antidepressant-receptor complex were highly correlated. Thus, the α7 nAChR is negatively modulated by a variety of antidepressants interacting in the ion−channel.

Highlights

Cholinergic pathway dysfunctions have been associated with pathologies, such as Alzheimer’s disease, addiction, depressive disorders, and schizophrenia, among others [1,2,3,4]
We developed a homology model structure for the rat α7 nicotinic acetylcholine receptors (nAChRs) to study the main interactions of the selected antidepressants
It was considered that omission of these unmodelled residues does not affect functional properties of the human α4β2 nAChR [10]. It is not discarded, the possibility that antidepressants interact at the orthosteric site (for imipramine and escitalopram at the (α9)2(α10)3 nAChR) [12,13], the present study focuses on the interaction between antidepressants and the α7 nAChR, which takes place within the ion channel, lined by the M2 transmembrane segment of each subunit, which is a common binding site of the most studied antidepressant [12,15,17]

Summary

Introduction

Cholinergic pathway dysfunctions have been associated with pathologies, such as Alzheimer’s disease, addiction, depressive disorders, and schizophrenia, among others [1,2,3,4]. With regard to depressive disorders, hyperactivation of the cholinergic pathway by nicotinic acetylcholine receptor (nAChR) agonists or acetylcholinesterase inhibitors brings forward depression in patients, even in adolescents [5,6,7,8]. NAChRs are pentameric proteins made up of the combination of α2–α10 and β2–β4 subunits, or forming homomeric receptors with a single subunit. No model is available for the complete rat α7 nAChR, the X-ray structure of the human α4β2 nAChR has been obtained recently, as well. Molecules 2021, 26, 998 rat α7 nAChR, the X-ray structure of the human α4β2 nAChR has been obtained rec2eonft1l5y, as well as homology models developed for the human α7 nAChR using protein structures with high sequence identity with this receptor as templates [10,11]. TThhuuss,,ththeeaaimimssooffththisiswwoorrkkwweerree(a(a))totostsutuddyyfufunncctitoionnaallininhhibibitiotorryyeefffefecctstsooffsesevveeraral l aanntitdideeppreressssaanntstswwitihthddiffifefreernetncthcehmemicaiclasltrsutrcutuctruerseasnadnpdhpahrmaramcoalcoogloicgailcpalropfirloefsil(eFsig(Fuirgeu1r)e o1n) roant rhaitphpiopcpaomcapmalpαa7l αn7AnCAhCRhsR, (sb,)(bto) tboubiludilad3aD3Dstrsutrcutcutruarlaml modoedleol fotfhteherartatαα77nnAACChhRR bbyyhhoommoollooggyy mmooddeelliinngg,, aanndd ((cc)) ttoo ccoorrrreellaatteebbootthhfufunncctitoionnaal l(e(leelcetcrtoropphhysyisoiloolgoigciacla)la) nadndin insilsiicloicoapapprporaocahcehses(m(moolelceuculalrarddoocckkininggaanndd mmoolleeccuullaarr ddyynnaammiiccss ((MMDD))ssimimuulalattioionnssaanndd bbininddiningg--ffrreeeeeenneerrggyyccaalclcuulalatitoionnss))foforrththeeaanntitdideeppreresssasannt-tr-erecceepptotorrininteteraracctitoionn. .TThhisissstutuddyy aaccqquuirireessrreelelevvaanncceeinintthheesseennsseetthhaattititccoonnttrribibuutteessttootthheeuunnddeerrssttaannddiinnggoofftthheessttrruuccttuurree-ffuunncctitoionnrreelalatitoionnsshhipipssooffnnAACChhRRssaannddththeeppaarrtitcicipipaatitoionnooffththeesseerreecceepptotorsrs, ,ppaarrtitcicuulalarlrylyththee αα77nnAACChhRR,,ininththeecclilninicicaalltrtreeaatmtmeennttooffmmaajojorrddeeppreresssisoionn

Methods

Results

Conclusion