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Interaction of Selective Serotonin Reuptake Inhibitors with Neuronal Nicotinic Acetylcholine Receptors

Arias, HR and Feuerbach, Dominik and Targowska-Duda, KM and Russell, M and Jozwiak, K (2010) Interaction of Selective Serotonin Reuptake Inhibitors with Neuronal Nicotinic Acetylcholine Receptors. Biochemistry.

Abstract

ABSTRACT: We compared the interaction of fluoxetine and paroxetine, two selective serotonin reuptake inhibitors (SSRIs), with the human (h) α4β2, α3β4, and α7 nicotinic acetylcholine receptors (AChRs) in different conformational states. The results established that: (1) fluoxetine was more potent than paroxetine in inhibiting agonist-activated Ca2+ influx on hα4β2 and hα3β4 AChRs. However, paroxetine was more potent in the hα7 AChR, (2) SSRIs bind to the [3H]imipramine locus with higher affinity when the AChRs are in the desensitized states compared to the resting states, (3) the different receptor specificity for fluoxetine determined by their inhibitory potencies or binding affinities suggests different modes of interaction when the AChR is in the closed or activated state, and (4) neutral and protonated fluoxetine interacts with a binding domain formed by M2 helix channel lining residues numbered from the cytoplasmic end as positions 6’ and 13’. In conclusion, SSRIs inhibit the most important neuronal AChRs with potencies and affinities that are clinically relevant by binding to a luminal site that is shared with tricyclic antidepressants.

Item Type: Article
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/3120

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