Muscle-Type Nicotinic Receptor Blockade by Diethylamine, the Hydrophilic Moiety of Lidocaine

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Título: Muscle-Type Nicotinic Receptor Blockade by Diethylamine, the Hydrophilic Moiety of Lidocaine
Autor/es: Alberola-Die, Armando | Fernández-Ballester, Gregorio | González-Ros, José M. | Ivorra, Isabel | Morales, Andrés
Grupo/s de investigación o GITE: Fisiología de Membranas
Centro, Departamento o Servicio: Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología
Palabras clave: Diethylamine | Lidocaine | Nicotinic acetylcholine receptors | Xenopus oocytes | Microtransplanted receptors | Allosteric modulation
Área/s de conocimiento: Fisiología
Fecha de publicación: 15-feb-2016
Editor: Frontiers Media
Cita bibliográfica: Alberola-Die A, Fernández-Ballester G, González-Ros JM, Ivorra I and Morales A (2016) Muscle-Type Nicotinic Receptor Blockade by Diethylamine, the Hydrophilic Moiety of Lidocaine. Front. Mol. Neurosci. 9:12. doi: 10.3389/fnmol.2016.00012
Resumen: Lidocaine bears in its structure both an aromatic ring and a terminal amine, which can be protonated at physiological pH, linked by an amide group. Since lidocaine causes multiple inhibitory actions on nicotinic acetylcholine receptors (nAChRs), this work was aimed to determine the inhibitory effects of diethylamine (DEA), a small molecule resembling the hydrophilic moiety of lidocaine, on Torpedo marmorata nAChRs microtransplanted to Xenopus oocytes. Similarly to lidocaine, DEA reversibly blocked acetylcholine-elicited currents (IACh) in a dose-dependent manner (IC50 close to 70 μM), but unlike lidocaine, DEA did not affect IACh desensitization. IACh inhibition by DEA was more pronounced at negative potentials, suggesting an open-channel blockade of nAChRs, although roughly 30% inhibition persisted at positive potentials, indicating additional binding sites outside the pore. DEA block of nAChRs in the resting state (closed channel) was confirmed by the enhanced IACh inhibition when pre-applying DEA before its co-application with ACh, as compared with solely DEA and ACh co-application. Virtual docking assays provide a plausible explanation to the experimental observations in terms of the involvement of different sets of drug binding sites. So, at the nAChR transmembrane (TM) domain, DEA and lidocaine shared binding sites within the channel pore, giving support to their open-channel blockade; besides, lidocaine, but not DEA, interacted with residues at cavities among the M1, M2, M3, and M4 segments of each subunit and also at intersubunit crevices. At the extracellular (EC) domain, DEA and lidocaine binding sites were broadly distributed, which aids to explain the closed channel blockade observed. Interestingly, some DEA clusters were located at the α-γ interphase of the EC domain, in a cavity near the orthosteric binding site pocket; by contrast, lidocaine contacted with all α-subunit loops conforming the ACh binding site, both in α-γ and α-δ and interphases, likely because of its larger size. Together, these results indicate that DEA mimics some, but not all, inhibitory actions of lidocaine on nAChRs and that even this small polar molecule acts by different mechanisms on this receptor. The presented results contribute to a better understanding of the structural determinants of nAChR modulation.
Patrocinador/es: This work was supported by grants BFU2012-31359, BFU2012-39092-C02-01, BFU2011-25920, and CSD2008-00005 from the MINECO and PROMETEO/2014/11 from GVA (Spain).
ISSN: 1662-5099
DOI: 10.3389/fnmol.2016.00012
Idioma: eng
Tipo: info:eu-repo/semantics/article
Derechos: © 2016 Alberola-Die, Fernández-Ballester, González-Ros, Ivorra and Morales. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Revisión científica: si
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Aparece en las colecciones:INV - Fisiología de Membranas - Artículos de Revistas

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