(−)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites |
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Authors: | Hugo R Arias Marcelo O Ortells Dominik Feuerbach |
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Institution: | 1. Department of Medical Education, California Northstate University College of Medicine, Elk Grove, CA, USA;2. Faculty of Medicine and CONICET, University of Morón, Argentina;3. Novartis Institutes for Biomedical Research, Basel, Switzerland |
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Abstract: | 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 (hα1β1γδ) and adult (hα1β1εδ) AChRs in a non-competitive manner and with potencies IC50 = 3.86 ± 0.49 and 1.92 ± 0.48 μM, respectively, (b) binds to the 3H]TCP site with ∼13-fold higher affinity when the Torpedo AChR is in the desensitized state compared to the resting state, (c) enhances 3H]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 γ subunit, and at the α1/ε 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. |
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Keywords: | AChR nicotinic acetylcholine receptor NSRI norepinephrine selective reuptake inhibitor TCAs tricyclic antidepressants NCA non-competitive antagonist (&minus )-reboxetine (&minus )-R R-([2-[α[2-ethoxyphenoxy]benzyl]-morpholine) PCP phencyclidine [3H]TCP piperidyl-3 4-3H(N)]-(N-(1-(2 thienyl)cyclohexyl)-3 4-piperidine CCh carbamylcholine α-BTx α-bungarotoxin RT room temperature BS binding saline Ki inhibition constant IC50 ligand concentration that inhibits 50% binding or ion flux EC50 ligand concentration that produces 50% increase of binding nH Hill coefficient DMEM dulbecco&rsquo s modified eagle medium FBS fetal bovine serum RMSD root mean square deviation |
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