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dc.contributor.author
Rayes, Diego Hernán
dc.contributor.author
de Rosa, Maria Jose
dc.contributor.author
Bartos, Mariana
dc.contributor.author
Bouzat, Cecilia Beatriz
dc.date.available
2018-07-26T22:26:35Z
dc.date.issued
2004-08-26
dc.identifier.citation
Rayes, Diego Hernán; de Rosa, Maria Jose; Bartos, Mariana; Bouzat, Cecilia Beatriz; Molecular basis of the differential sensitivity of nematode and mammalian muscle to the anthelmintic agent levamisole; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 279; 35; 26-8-2004; 36372-36381
dc.identifier.issn
0021-9258
dc.identifier.uri
http://hdl.handle.net/11336/53269
dc.description.abstract
Levamisole is an anthelmintic agent that exerts its therapeutic effect by acting as a fall agonist of the nicotinic receptor (AChR) of nematode muscle. Its action at the mammalian muscle AChR has not been elucidated to date despite its wide use as an anthelmintic in humans and cattle. By single channel and macroscopic current recordings, we investigated the interaction of levamisole with the mammalian muscle AChR. Levamisole activates mammalian AChRs. However, single channel openings are briefer than those activated by acetylcholine (ACh) and do not appear in clusters at high concentrations. The peak current induced by levamisole is about 3% that activated by ACh. Thus, the anthelmintic acts as a weak agonist of the mammalian AChR. Levamisole also produces open channel blockade of the AChR. The apparent affinity for block (190 μM at -70 mV) is similar to that of the nematode AChR, suggesting that differences in channel activation kinetics govern the different sensitivity of nematode and mammalian muscle to anthelmintics. To identify the structural basis of this different sensitivity, we performed mutagenesis targeting residues in the α subunit that differ between vertebrates and nematodes. The replacement of the conserved αGly-153 with the homologous glutamic acid of nematode AChR significantly increases the efficacy of levamisole to activate channels. Channel activity takes place in clusters having two different kinetic modes. The kinetics of the high open probability mode are almost identical when the agonist is ACh or levamisole. It is concluded that αGly-153 is involved in the low efficacy of levamisole to activate mammalian muscle AChRs.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Society for Biochemistry and Molecular Biology
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by/2.5/ar/
dc.subject.classification
Otras Ciencias Biológicas
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Molecular basis of the differential sensitivity of nematode and mammalian muscle to the anthelmintic agent levamisole
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-07-11T14:17:21Z
dc.journal.volume
279
dc.journal.number
35
dc.journal.pagination
36372-36381
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Bethesda
dc.description.fil
Fil: Rayes, Diego Hernán. 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: de Rosa, Maria Jose. 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: Bartos, Mariana. 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: 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
Journal of Biological Chemistry (online)
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/content/279/35/36372.full
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1074/jbc.M403096200
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