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Functional and Structural Interaction of (-)-Reboxetine with the Human alpha4beta2 Nicotinic Acetylcholine Receptor

Arias, HR, Fedorov, NB, Benson, LC, Lippiello, PM, Gatto, GJ, Feuerbach, Dominik and Ortells, MC (2013) Functional and Structural Interaction of (-)-Reboxetine with the Human alpha4beta2 Nicotinic Acetylcholine Receptor. Journal of Pharmacology and experimental therapeutics, 344 (3). pp. 113-123. ISSN 112.197905


The interaction of the selective norepinephrine reuptake inhibitor, (-)-reboxetine, with the human (h) α4β2 nicotinic acetylcholine receptor (nAChR) in different conformational states was studied by several functional and structural approaches. Patch-clamp and Ca2+-influx results indicate that (-)-reboxetine does not activate hα4β2 nAChRs via interaction with the orthosteric sites, but inhibits agonist-induced hα4β2 activation by a noncompetitive mechanism. Consistently, the results from the electrophysiology-based functional approach suggest that (-)-reboxetine may act via open channel block, so it is capable of producing a use-dependent type of inhibition of the hα4β2 nAChR function. We tested whether (-)-reboxetine binds to the luminal [3H]imipramine site. The results indicate that although (-)-reboxetine binds with low affinity to this site, it discriminates between the resting and desensitized hα4β2 nAChR ion channels. Patch-clamp results also indicate that (-)-reboxetine progressively inhibits the hα4β2 nAChR with 2-fold higher potency at the end of 1-s application of agonist compared to the peak current. The molecular docking studies show that (-)-reboxetine blocks the ion channel at the level of the imipramine locus, between M2 rings 6’ and 14’. Additionally, we found a (-)-reboxetine conformer that docks within the helix bundle of the α4 subunit, near the middle region. According to molecular dynamics simulations, (-)-reboxetine binding is stable for both sites, albeit less stable than imipramine. The interaction of these drugs with the helix bundle might alter allostericaly the functionality of the channel. In conclusion, the clinical action of (-)-reboxetine may be produced (at least partially) by its inhibitory action on hα4β2 nAChRs.

Item Type: Article
Date Deposited: 13 Oct 2016 00:45
Last Modified: 13 Oct 2016 00:45


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