TY - JOUR
T1 - Tricyclic antidepressants inhibit hippocampal α7* and α9α10 nicotinic acetylcholine receptors by different mechanisms
AU - Arias, Hugo R.
AU - Vázquez-Gómez, Elizabeth
AU - Hernández-Abrego, Andy
AU - Gallino, Sofía
AU - Feuerbach, Dominik
AU - Ortells, Marcelo O.
AU - Elgoyhen, Ana Belén
AU - García-Colunga, Jesús
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/7/1
Y1 - 2018/7/1
N2 - The activity of tricyclic antidepressants (TCAs) at α7 and α9α10 nicotinic acetylcholine receptors (AChRs) as well as at hippocampal α7-containing (i.e., α7*) AChRs is determined by using Ca 2+ influx and electrophysiological recordings. To determine the inhibitory mechanisms, additional functional tests and molecular docking experiments are performed. The results established that TCAs (a) inhibit Ca 2+ influx in GH3-α7 cells with the following potency (IC 50 in μM) rank: amitriptyline (2.7 ± 0.3) > doxepin (5.9 ± 1.1) ∼ imipramine (6.6 ± 1.0). Interestingly, imipramine inhibits hippocampal α7* AChRs (42.2 ± 8.5 μM) in a noncompetitive and voltage-dependent manner, whereas it inhibits α9α10 AChRs (0.53 ± 0.05 μM) in a competitive and voltage-independent manner, and (b) inhibit [ 3 H]imipramine binding to resting α7 AChRs with the following affinity rank (IC 50 in μM): imipramine (1.6 ± 0.2) > amitriptyline (2.4 ± 0.3) > doxepin (4.9 ± 0.6), whereas imipramine's affinity was no significantly different to that for the desensitized state. The molecular docking and functional results support the notion that imipramine noncompetitively inhibits α7 AChRs by interacting with two overlapping luminal sites, whereas it competitively inhibits α9α10 AChRs by interacting with the orthosteric sites. Collectively our data indicate that TCAs inhibit α7, α9α10, and hippocampal α7* AChRs at clinically relevant concentrations and by different mechanisms of action.
AB - The activity of tricyclic antidepressants (TCAs) at α7 and α9α10 nicotinic acetylcholine receptors (AChRs) as well as at hippocampal α7-containing (i.e., α7*) AChRs is determined by using Ca 2+ influx and electrophysiological recordings. To determine the inhibitory mechanisms, additional functional tests and molecular docking experiments are performed. The results established that TCAs (a) inhibit Ca 2+ influx in GH3-α7 cells with the following potency (IC 50 in μM) rank: amitriptyline (2.7 ± 0.3) > doxepin (5.9 ± 1.1) ∼ imipramine (6.6 ± 1.0). Interestingly, imipramine inhibits hippocampal α7* AChRs (42.2 ± 8.5 μM) in a noncompetitive and voltage-dependent manner, whereas it inhibits α9α10 AChRs (0.53 ± 0.05 μM) in a competitive and voltage-independent manner, and (b) inhibit [ 3 H]imipramine binding to resting α7 AChRs with the following affinity rank (IC 50 in μM): imipramine (1.6 ± 0.2) > amitriptyline (2.4 ± 0.3) > doxepin (4.9 ± 0.6), whereas imipramine's affinity was no significantly different to that for the desensitized state. The molecular docking and functional results support the notion that imipramine noncompetitively inhibits α7 AChRs by interacting with two overlapping luminal sites, whereas it competitively inhibits α9α10 AChRs by interacting with the orthosteric sites. Collectively our data indicate that TCAs inhibit α7, α9α10, and hippocampal α7* AChRs at clinically relevant concentrations and by different mechanisms of action.
KW - Electrophysiology
KW - Hippocampal neurons
KW - Mechanisms of inhibition
KW - Tricyclic antidepressants
KW - α7 and α9α10 nicotinic acetylcholine receptors
UR - http://www.scopus.com/inward/record.url?scp=85046666947&partnerID=8YFLogxK
U2 - 10.1016/j.biocel.2018.04.017
DO - 10.1016/j.biocel.2018.04.017
M3 - Article
C2 - 29704625
AN - SCOPUS:85046666947
SN - 1357-2725
VL - 100
SP - 1
EP - 10
JO - International Journal of Biochemistry and Cell Biology
JF - International Journal of Biochemistry and Cell Biology
ER -