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

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.

Regulation of Hippocampal GABAergic Transmission by Fluoxetine and Its Metabolite Norfluoxetine

“…Assuming that both fluoxetine and norfluoxetine modulate different targets in addition to serotonin transport, another feasible way to explain the decrease in the frequency of sIPSCs in hippocampal stratum radiatum interneurons may be through their interaction with nicotinic acetylcholine receptors, Ca 2+ -permeable AMPA receptors, and/or T-type calcium channels [37,38,42,43]. It is known that both fluoxetine and norfluoxetine inhibit nicotinic acetylcholine receptors in a non-competitive manner [39][40][41]; in this context, interneurons of the hippocampal CA1 stratum radiatum selectively express the α7 nicotinic receptor, which is highly permeable to Ca 2+ [61,62]. Therefore, the possible inhibition of all of these membrane proteins by fluoxetine and norfluoxetine in cells that establish synapses with stratum radiatum interneurons would lead to a decrease in GABA release, with the consequent disinhibition of stratum radiatum interneurons.…”

“…In this context, fluoxetine inhibits N-methyl-D-aspartate (NMDA) and Ca 2+ -permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) glutamate receptors in the neurons of the hippocampal CA1 area [37] and decreases the expression of the GluA4 AMPA receptor subunit in the GABAergic parvalbumin-positive interneurons of the prefrontal cortex [38]. Furthermore, fluoxetine and norfluoxetine inhibit, in a non-competitive manner, nicotinic acetylcholine receptors, including α7 nicotinic receptors, which are highly permeable to Ca 2+ [39][40][41]. Likewise, fluoxetine and norfluoxetine also inhibit T-type Ca 2+ channels [42,43].…”

Antiviral phytocompounds “ellagic acid” and “(+)-sesamin” of Bridelia retusa identified as potential inhibitors of SARS-CoV-2 3CL pro using extensive molecular docking, molecular dynamics simulation studies, binding free energy calculations, and bioactivity prediction

“…The MD trajectories were generated by the Desmond module from Maestro-Schrodinger 2021–3. As described by Duarte et al (2021) and Mahmoud et al (2021), the calculations of the average MM-GBSA binding free energy in Desmond MD trajectory (*-cms.out) was carried out by executing the thermal_mmgbsa.py script of Schrodinger [ 42 , 43 ]. The thermal script processed the MD trajectory of Desmond and splits it into 1001 individual frame snapshots that were used as input to compute the average binding free energy and each individual snapshot runs through MM-GBSA analysis.…”

Recent Advances in the Modulation of Cholinergic Signaling

“…Three research articles focus on studies involving the α7 nicotinic acetylcholine receptor (nAChR) signaling [6][7][8]. Salazar Intriago et al [6] established that the selective activation of the α7 receptor may be relevant for the microenvironment favorable for improving peripheral nerve regeneration.…”

“…Duarte et al [8] evaluated the rat α7 nAChR modulation via seven antidepressants (norfluoxetine, mirtazapine, imipramine, bupropion, fluoxetine, venlafaxine, and escitalopram) with different structures and pharmacological profiles. The investigation was performed by employing electrophysiological assays and molecular docking and dynamics simulations.…”