Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors
- Autores
- Bartos, Mariana; Rayes, Diego Hernán; Bouzat, Cecilia Beatriz
- Año de publicación
- 2006
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Nicotinic receptors (AChRs) play key roles in synaptic transmission throughout the nervous system. AChRs mediate neuromuscular transmission in nematodes and they are targets for antiparasitic drugs. The anthelmintic agents levamisole and pyrantel, which are potent agonists of nematode muscle AChRs, are partial agonists of mammalian muscle AChRs. To further explore the structural basis of the differential activation of AChR subtypes by anthelmintics, we studied the activation of alpha7 AChRs using the high conductance form of the alpha7-5HT3A receptor, which is a good model for pharmacological studies involving the extracellular region of alpha7. Macroscopic and single-channel current recordings show that levamisole is a weak agonist of alpha7. Interestingly, pyrantel is a more potent agonist of alpha7 than ACh. To identify determinants of this differential activation, we replaced residues of the complementary face of the binding site by the homologous residues in the muscle epsilon subunit and evaluated changes in activation. The mutation Q57G does not affect the activation by either ACh or levamisole. However, it increases EC50 and decreases the maximal response to pyrantel. Kinetic analysis shows that gating of the mutant channel activated by pyrantel is profoundly impaired. The decreased sensitivity of alpha7-Q57G to pyrantel agrees with its weak action at muscle AChRs, indicating that when glycine occupies position 57, as in the mammalian muscle AChR, pyrantel behaves as a partial agonist. Thus, position 57 located at the complementary face of the binding site plays a key role in the selective activation of AChRs by pyrantel.
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
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
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 - Materia
-
CYS LOOP RECEPTOR
NICOTINIC RECEPTOR
PATCH CLAMP
ANTHELMINTIC - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/44392
Ver los metadatos del registro completo
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Molecular Determinants of Pyrantel Selectivity in Nicotinic ReceptorsBartos, MarianaRayes, Diego HernánBouzat, Cecilia BeatrizCYS LOOP RECEPTORNICOTINIC RECEPTORPATCH CLAMPANTHELMINTIChttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Nicotinic receptors (AChRs) play key roles in synaptic transmission throughout the nervous system. AChRs mediate neuromuscular transmission in nematodes and they are targets for antiparasitic drugs. The anthelmintic agents levamisole and pyrantel, which are potent agonists of nematode muscle AChRs, are partial agonists of mammalian muscle AChRs. To further explore the structural basis of the differential activation of AChR subtypes by anthelmintics, we studied the activation of alpha7 AChRs using the high conductance form of the alpha7-5HT3A receptor, which is a good model for pharmacological studies involving the extracellular region of alpha7. Macroscopic and single-channel current recordings show that levamisole is a weak agonist of alpha7. Interestingly, pyrantel is a more potent agonist of alpha7 than ACh. To identify determinants of this differential activation, we replaced residues of the complementary face of the binding site by the homologous residues in the muscle epsilon subunit and evaluated changes in activation. The mutation Q57G does not affect the activation by either ACh or levamisole. However, it increases EC50 and decreases the maximal response to pyrantel. Kinetic analysis shows that gating of the mutant channel activated by pyrantel is profoundly impaired. The decreased sensitivity of alpha7-Q57G to pyrantel agrees with its weak action at muscle AChRs, indicating that when glycine occupies position 57, as in the mammalian muscle AChR, pyrantel behaves as a partial agonist. Thus, position 57 located at the complementary face of the binding site plays a key role in the selective activation of AChRs by pyrantel.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; ArgentinaFil: 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; ArgentinaFil: 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; ArgentinaAmerican Society for Pharmacology and Experimental Therapeutics2006-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/44392Bartos, Mariana; Rayes, Diego Hernán; Bouzat, Cecilia Beatriz; Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 70; 4; 12-2006; 1307-13180026-895XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1124/mol.106.026336info:eu-repo/semantics/altIdentifier/url/http://molpharm.aspetjournals.org/content/70/4/1307info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:07:32Zoai:ri.conicet.gov.ar:11336/44392instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:07:32.497CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors |
title |
Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors |
spellingShingle |
Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors Bartos, Mariana CYS LOOP RECEPTOR NICOTINIC RECEPTOR PATCH CLAMP ANTHELMINTIC |
title_short |
Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors |
title_full |
Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors |
title_fullStr |
Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors |
title_full_unstemmed |
Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors |
title_sort |
Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors |
dc.creator.none.fl_str_mv |
Bartos, Mariana Rayes, Diego Hernán Bouzat, Cecilia Beatriz |
author |
Bartos, Mariana |
author_facet |
Bartos, Mariana Rayes, Diego Hernán Bouzat, Cecilia Beatriz |
author_role |
author |
author2 |
Rayes, Diego Hernán Bouzat, Cecilia Beatriz |
author2_role |
author author |
dc.subject.none.fl_str_mv |
CYS LOOP RECEPTOR NICOTINIC RECEPTOR PATCH CLAMP ANTHELMINTIC |
topic |
CYS LOOP RECEPTOR NICOTINIC RECEPTOR PATCH CLAMP ANTHELMINTIC |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
Nicotinic receptors (AChRs) play key roles in synaptic transmission throughout the nervous system. AChRs mediate neuromuscular transmission in nematodes and they are targets for antiparasitic drugs. The anthelmintic agents levamisole and pyrantel, which are potent agonists of nematode muscle AChRs, are partial agonists of mammalian muscle AChRs. To further explore the structural basis of the differential activation of AChR subtypes by anthelmintics, we studied the activation of alpha7 AChRs using the high conductance form of the alpha7-5HT3A receptor, which is a good model for pharmacological studies involving the extracellular region of alpha7. Macroscopic and single-channel current recordings show that levamisole is a weak agonist of alpha7. Interestingly, pyrantel is a more potent agonist of alpha7 than ACh. To identify determinants of this differential activation, we replaced residues of the complementary face of the binding site by the homologous residues in the muscle epsilon subunit and evaluated changes in activation. The mutation Q57G does not affect the activation by either ACh or levamisole. However, it increases EC50 and decreases the maximal response to pyrantel. Kinetic analysis shows that gating of the mutant channel activated by pyrantel is profoundly impaired. The decreased sensitivity of alpha7-Q57G to pyrantel agrees with its weak action at muscle AChRs, indicating that when glycine occupies position 57, as in the mammalian muscle AChR, pyrantel behaves as a partial agonist. Thus, position 57 located at the complementary face of the binding site plays a key role in the selective activation of AChRs by pyrantel. 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 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 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 |
description |
Nicotinic receptors (AChRs) play key roles in synaptic transmission throughout the nervous system. AChRs mediate neuromuscular transmission in nematodes and they are targets for antiparasitic drugs. The anthelmintic agents levamisole and pyrantel, which are potent agonists of nematode muscle AChRs, are partial agonists of mammalian muscle AChRs. To further explore the structural basis of the differential activation of AChR subtypes by anthelmintics, we studied the activation of alpha7 AChRs using the high conductance form of the alpha7-5HT3A receptor, which is a good model for pharmacological studies involving the extracellular region of alpha7. Macroscopic and single-channel current recordings show that levamisole is a weak agonist of alpha7. Interestingly, pyrantel is a more potent agonist of alpha7 than ACh. To identify determinants of this differential activation, we replaced residues of the complementary face of the binding site by the homologous residues in the muscle epsilon subunit and evaluated changes in activation. The mutation Q57G does not affect the activation by either ACh or levamisole. However, it increases EC50 and decreases the maximal response to pyrantel. Kinetic analysis shows that gating of the mutant channel activated by pyrantel is profoundly impaired. The decreased sensitivity of alpha7-Q57G to pyrantel agrees with its weak action at muscle AChRs, indicating that when glycine occupies position 57, as in the mammalian muscle AChR, pyrantel behaves as a partial agonist. Thus, position 57 located at the complementary face of the binding site plays a key role in the selective activation of AChRs by pyrantel. |
publishDate |
2006 |
dc.date.none.fl_str_mv |
2006-12 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/44392 Bartos, Mariana; Rayes, Diego Hernán; Bouzat, Cecilia Beatriz; Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 70; 4; 12-2006; 1307-1318 0026-895X CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/44392 |
identifier_str_mv |
Bartos, Mariana; Rayes, Diego Hernán; Bouzat, Cecilia Beatriz; Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 70; 4; 12-2006; 1307-1318 0026-895X CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1124/mol.106.026336 info:eu-repo/semantics/altIdentifier/url/http://molpharm.aspetjournals.org/content/70/4/1307 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
American Society for Pharmacology and Experimental Therapeutics |
publisher.none.fl_str_mv |
American Society for Pharmacology and Experimental Therapeutics |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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13.13397 |