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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/44392

id CONICETDig_9aa284d67639dc8a48aa07826b88d6ec
oai_identifier_str oai:ri.conicet.gov.ar:11336/44392
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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
_version_ 1842270006008610816
score 13.13397