Paper Citing NAMD - Abstract
Arias, Hugo R.; Ortells, Marcelo O.; Feuerbach, Dominik
(-)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites
NEUROCHEMISTRY INTERNATIONAL, 63:423-431, NOV 2013
The interaction of (-)-reboxetine, a non-tricyclic norepinephrine selective reuptake inhibitor, with muscle-type nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that (-)-reboxetine: (a) inhibits (+/-)-epibatidine-induced Ca2+ influx in human (h) muscle embryonic (h alpha 1 beta 1 gamma delta) and adult (h alpha 1 beta 1 epsilon delta) AChRs in a non-competitive manner and with potencies IC50 = 3.86 +/- 0.49 and 1.92 +/- 0.48 mu M, respectively, (b) binds to the [H-3]TCP site with similar to 13-fold higher affinity when the Torpedo AChR is in the desensitized state compared to the resting state, (c) enhances [H-3]cytisine binding to the resting but activatableTorpedo AChR but not to the desensitized AChR, suggesting desensitizing properties, (d) overlaps the PCP luminal site located between rings 6' and 13' in the Torpedo but not human muscle AChRs. In silico mutation results indicate that ring 9' is the minimum structural component for (-)-reboxetine binding, and (e) interacts to non-luminal sites located within the transmembrane segments from the Torpedo AChR gamma subunit, and at the alpha 1/epsilon transmembrane interface from the adult muscle AChR. In conclusion, (-)-reboxetine non-competitively inhibits muscle AChRs by binding to the TCP luminal site and by inducing receptor desensitization (maybe by interacting with non-luminal sites), a mechanism that is shared by tricyclic antidepressants. (C) 2013 Elsevier Ltd. All rights reserved.
