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dc.contributor.author Spitzmaul, Guillermo Federico
dc.contributor.author Gumilar, Fernanda Andrea
dc.contributor.author Dilger, James P.
dc.contributor.author Bouzat, Cecilia Beatriz
dc.date.available 2018-04-13T14:40:05Z
dc.date.issued 2009-07
dc.identifier.citation Spitzmaul, Guillermo Federico; Gumilar, Fernanda Andrea; Dilger, James P.; Bouzat, Cecilia Beatriz; The local anaesthetics proadifen and adiphenine inhibit nicotinic receptors by different molecular mechanisms; Wiley Blackwell Publishing, Inc; British Journal of Pharmacology; 157; 5; 7-2009; 804-817
dc.identifier.issn 0007-1188
dc.identifier.uri http://hdl.handle.net/11336/41981
dc.description.abstract Background and purpose: Many local anaesthetics are non-competitive inhibitors of nicotinic receptors (acetylcholine receptor, AChR). Proadifen induces a high-affinity state of the receptor, but its mechanism of action and that of an analogue, adiphenine, is unknown. Experimental approach: We measured the effects of proadifen and adiphenine on single-channel and macroscopic currents of adult mouse muscle AChR (wild-type and mutant). We assessed the results in terms of mechanisms and sites of action. Key results: Both proadifen and adiphenine decreased the frequency of ACh-induced single-channel currents. Proadifen did not change cluster properties, but adiphenine decreased cluster duration (36-fold at 100 mmol·L-1). Preincubation with proadifen decreased the amplitude (IC50 = 19 mmol·L-1) without changing the decay rate of macroscopic currents. In contrast, adiphenine did not change amplitude but increased the decay rate (IC50 = 15 mmol·L-1). Kinetic measurements demonstrate that proadifen acts on the resting state to induce a desensitized state whose kinetics of recovery resemble those of ACh-induced desensitization. Adiphenine accelerates desensitization from the open state, but previous application of the drug to resting receptors is required. Both drugs stabilize desensitized states, as evidenced by the decrease in the number of clusters elicited by high ACh concentrations. The inhibition by adiphenine is not affected by proadifen, and the mutation aE262K decreases the sensitivity of the AChR only for adiphenine, indicating that these drugs act at different sites. Conclusions and implications: Two analogous local anaesthetics bind to different sites and inhibit AChR activity via different mechanisms and conformational states. These results provide new information on drug modulation of AChR.
dc.format application/pdf
dc.language.iso eng
dc.publisher Wiley Blackwell Publishing, Inc
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject ACETYLCHOLINE RECEPTOR
dc.subject NON-COMPETITIVE INHIBITORS
dc.subject PROADIFEN
dc.subject LOCAL ANAESTHETICS
dc.subject.classification Otras Ciencias Biológicas
dc.subject.classification Ciencias Biológicas
dc.subject.classification CIENCIAS NATURALES Y EXACTAS
dc.title The local anaesthetics proadifen and adiphenine inhibit nicotinic receptors by different molecular mechanisms
dc.type info:eu-repo/semantics/article
dc.type info:ar-repo/semantics/artículo
dc.type info:eu-repo/semantics/publishedVersion
dc.date.updated 2018-04-05T18:24:19Z
dc.journal.volume 157
dc.journal.number 5
dc.journal.pagination 804-817
dc.journal.pais Reino Unido
dc.journal.ciudad Londres
dc.description.fil Fil: Spitzmaul, Guillermo Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
dc.description.fil Fil: Gumilar, Fernanda Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
dc.description.fil Fil: Dilger, James P.. Stony Brook University; Estados Unidos
dc.description.fil Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
dc.journal.title British Journal of Pharmacology
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1111/j.1476-5381.2009.00214.x
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/url/https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1476-5381.2009.00214.x
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info:eu-repo/semantics/restrictedAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)