TY - JOUR
T1 - (-)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites
AU - Arias, Hugo R.
AU - Ortells, Marcelo O.
AU - Feuerbach, Dominik
N1 - Funding Information:
This research was supported by a grant from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET; Argentina) (to M.O.O.). The authors thank to National Institute on Drug Addiction (NIDA, NIH, Bethesda, Maryland, USA) for its gift of phencyclidine.
PY - 2013/8/30
Y1 - 2013/8/30
N2 - 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 (hα1β1ε δ) 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.
AB - 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 (hα1β1ε δ) 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.
KW - Antidepressants
KW - Conformational states
KW - Nicotinic acetylcholine receptors
KW - Norepinephrine selective reuptake inhibitor
KW - Reboxetine
UR - http://www.scopus.com/inward/record.url?scp=84882809457&partnerID=8YFLogxK
U2 - 10.1016/j.neuint.2013.07.009
DO - 10.1016/j.neuint.2013.07.009
M3 - Article
C2 - 23917086
AN - SCOPUS:84882809457
SN - 0197-0186
VL - 63
SP - 423
EP - 431
JO - Neurochemistry International
JF - Neurochemistry International
IS - 5
ER -