Mechanisms of Blockade of the Muscle-Type Nicotinic Receptor by Benzocaine, a Permanently Uncharged Local Anesthetic

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Title: Mechanisms of Blockade of the Muscle-Type Nicotinic Receptor by Benzocaine, a Permanently Uncharged Local Anesthetic
Authors: Cobo, Raúl | Nikolaeva-Koleva, Magdalena | Alberola-Die, Armando | Fernández-Ballester, Gregorio | González-Ros, José M. | Ivorra, Isabel | Morales, Andrés
Research Group/s: Fisiología de Membranas
Center, Department or Service: Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología
Keywords: Xenopus oocytes | Desensitization | Open-channel blockade | Closed-channel blockade | Rebound currents | Virtual-docking assays
Knowledge Area: Fisiología
Issue Date: 15-Jul-2020
Publisher: Elsevier
Citation: Neuroscience. 2020, 439: 62-79. doi:10.1016/j.neuroscience.2019.05.043
Abstract: Most local anesthetics (LAs) are amine compounds bearing one or several phenolic rings. Many of them are protonated at physiological pH, but benzocaine (Bzc) is permanently uncharged, which is relevant because the effects of LAs on nicotinic acetylcholine (ACh) receptors (nAChRs) depend on their presence as uncharged or protonated species. The aims of this study were to assess the effects of Bzc on nAChRs and to correlate them with its binding to putative interacting sites on this receptor. nAChRs from Torpedo electroplaques were microtransplanted to Xenopus oocytes and currents elicited by ACh (IAChs), either alone or together with Bzc, were recorded at different potentials. Co-application of ACh with increasing concentrations of Bzc showed that Bzc reversibly blocked nAChRs. IACh inhibition by Bzc was voltage-independent, but the IACh rebound elicited when rinsing Bzc suggests an open-channel blockade. Besides, ACh and Bzc co-application enhanced nAChR desensitization. When Bzc was just pre-applied it also inhibited IACh, by blocking closed (resting) nAChRs. This blockade slowed down the kinetics of both the IACh activation and the recovery from blockade. The electrophysiological results indicate that Bzc effects on nAChRs are similar to those of 2,6-dimethylaniline, an analogue of the hydrophobic moiety of lidocaine. Furthermore, docking assays on models of the nAChR revealed that Bzc and DMA binding sites on nAChRs overlap fairly well. These results demonstrate that Bzc inhibits nAChRs by multiple mechanisms and contribute to better understanding both the modulation of nAChRs and how LAs elicit some of their clinical side effects.
Sponsor: This work was supported by grants BFU2012-31359, BFU2015-66612-P, SAF2015-66275-C2-1-R and SAF2017-82977-P (AEI/FEDER, UE) from MINECO, PROMETEO/2014/11 from Generalitat Valenciana (Spain) and GRE17-01 from Universidad de Alicante. R.C. held a predoctoral fellowship from Universidad de Alicante (FPUUA36) and M.N. a predoctoral industrial fellowship from Ministerio de Economía, Industria y Competitividad (DI-16-08303).
URI: http://hdl.handle.net/10045/107949
ISSN: 0306-4522 (Print) | 1873-7544 (Online)
DOI: 10.1016/j.neuroscience.2019.05.043
Language: eng
Type: info:eu-repo/semantics/article
Rights: © 2019 IBRO. Published by Elsevier Ltd.
Peer Review: si
Publisher version: https://doi.org/10.1016/j.neuroscience.2019.05.043
Appears in Collections:INV - Fisiología de Membranas - Artículos de Revistas

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