Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors

Autores
Dionisio, Leonardo Raul; Bergé, Ignacio; Bravo, Matías; Esandi, María del Carmen; Bouzat, Cecilia Beatriz
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Cys-loop receptors are neurotransmitter-activated ion channels involved in synaptic and extrasynaptic transmission in the brain and are also present in non-neuronal cells. As GABAA and nicotinic receptors (nAChR) belong to this family, we explored by macroscopic and single-channel recordings whether the inhibitory neurotransmitter GABA has the ability to activate excitatory nAChRs. GABA differentially activates nAChR subtypes. It activates muscle nAChRs, with maximal peak currents of about 10% of those elicited by acetylcholine (ACh) and 15- fold higher EC50 with respect to ACh. At the single-channel level, the weak agonism is revealed by the requirement of 20-fold higher concentration of GABA for detectable channel openings, a major population of brief openings, and absence of clusters of openings when compared with ACh. Mutations at key residues of the principal binding-site face of muscle nAChRs (aY190 and aG153) affect GABA activation similarly as ACh activation, whereas a mutation at the complementary face (EG57) shows a selective effect for GABA. Studies with subunit-lacking receptors show that GABA can activate muscle nAChRs through the a/d interface. Interestingly, single-channel activity elicited by GABA is similar to that elicited by ACh in gain-of-function nAChR mutants associated to congenital myasthenic syndromes, which could be important in the progression of the disorders due to steady exposure to serum GABA. In contrast, GABA cannot elicit single-channel or macroscopic currents of a7 or the chimeric a7-serotonin-type 3 receptor, a feature important for preserving an adequate excitatory/inhibitory balance in the brain as well as for avoiding activation of nonneuronal receptors by serum GABA.
Fil: Dionisio, Leonardo Raul. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
Fil: Bergé, Ignacio. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
Fil: Bravo, Matías. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
Fil: Esandi, María del Carmen. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
Materia
NICOTINIC RECEPTOR
GABA
ACETYLCHOLINE
PATCH CLAMP
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/4378
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/4378
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Neurotransmitter GABA Activates Muscle but not a7 Nicotinic ReceptorsDionisio, Leonardo RaulBergé, IgnacioBravo, MatíasEsandi, María del CarmenBouzat, Cecilia BeatrizNICOTINIC RECEPTORGABAACETYLCHOLINEPATCH CLAMPhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Cys-loop receptors are neurotransmitter-activated ion channels involved in synaptic and extrasynaptic transmission in the brain and are also present in non-neuronal cells. As GABAA and nicotinic receptors (nAChR) belong to this family, we explored by macroscopic and single-channel recordings whether the inhibitory neurotransmitter GABA has the ability to activate excitatory nAChRs. GABA differentially activates nAChR subtypes. It activates muscle nAChRs, with maximal peak currents of about 10% of those elicited by acetylcholine (ACh) and 15- fold higher EC50 with respect to ACh. At the single-channel level, the weak agonism is revealed by the requirement of 20-fold higher concentration of GABA for detectable channel openings, a major population of brief openings, and absence of clusters of openings when compared with ACh. Mutations at key residues of the principal binding-site face of muscle nAChRs (aY190 and aG153) affect GABA activation similarly as ACh activation, whereas a mutation at the complementary face (EG57) shows a selective effect for GABA. Studies with subunit-lacking receptors show that GABA can activate muscle nAChRs through the a/d interface. Interestingly, single-channel activity elicited by GABA is similar to that elicited by ACh in gain-of-function nAChR mutants associated to congenital myasthenic syndromes, which could be important in the progression of the disorders due to steady exposure to serum GABA. In contrast, GABA cannot elicit single-channel or macroscopic currents of a7 or the chimeric a7-serotonin-type 3 receptor, a feature important for preserving an adequate excitatory/inhibitory balance in the brain as well as for avoiding activation of nonneuronal receptors by serum GABA.Fil: Dionisio, Leonardo Raul. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); ArgentinaFil: Bergé, Ignacio. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); ArgentinaFil: Bravo, Matías. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); ArgentinaFil: Esandi, María del Carmen. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); ArgentinaFil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); ArgentinaAmerican Society For Pharmacology And Experimental Therapeutics2015-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/4378Dionisio, Leonardo Raul; Bergé, Ignacio; Bravo, Matías; Esandi, María del Carmen; Bouzat, Cecilia Beatriz; Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors; American Society For Pharmacology And Experimental Therapeutics; Molecular Pharmacology; 87; 3-2015; 391-4000026-895Xenginfo:eu-repo/semantics/altIdentifier/ark/10.1124/mol.114.095539info:eu-repo/semantics/altIdentifier/url/http://molpharm.aspetjournals.org/content/suppl/2014/12/09/mol.114.095539.DC1.htmlinfo:eu-repo/semantics/altIdentifier/url/http://molpharm.aspetjournals.org/content/87/3/391.full.pdfinfo:eu-repo/semantics/altIdentifier/doi/10.1124/mol.114.095539info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:03:49Zoai:ri.conicet.gov.ar:11336/4378instacron: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 10:03:49.454CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors
title Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors
spellingShingle Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors
Dionisio, Leonardo Raul
NICOTINIC RECEPTOR
GABA
ACETYLCHOLINE
PATCH CLAMP
title_short Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors
title_full Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors
title_fullStr Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors
title_full_unstemmed Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors
title_sort Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors
dc.creator.none.fl_str_mv Dionisio, Leonardo Raul
Bergé, Ignacio
Bravo, Matías
Esandi, María del Carmen
Bouzat, Cecilia Beatriz
author Dionisio, Leonardo Raul
author_facet Dionisio, Leonardo Raul
Bergé, Ignacio
Bravo, Matías
Esandi, María del Carmen
Bouzat, Cecilia Beatriz
author_role author
author2 Bergé, Ignacio
Bravo, Matías
Esandi, María del Carmen
Bouzat, Cecilia Beatriz
author2_role author
author
author
author
dc.subject.none.fl_str_mv NICOTINIC RECEPTOR
GABA
ACETYLCHOLINE
PATCH CLAMP
topic NICOTINIC RECEPTOR
GABA
ACETYLCHOLINE
PATCH CLAMP
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Cys-loop receptors are neurotransmitter-activated ion channels involved in synaptic and extrasynaptic transmission in the brain and are also present in non-neuronal cells. As GABAA and nicotinic receptors (nAChR) belong to this family, we explored by macroscopic and single-channel recordings whether the inhibitory neurotransmitter GABA has the ability to activate excitatory nAChRs. GABA differentially activates nAChR subtypes. It activates muscle nAChRs, with maximal peak currents of about 10% of those elicited by acetylcholine (ACh) and 15- fold higher EC50 with respect to ACh. At the single-channel level, the weak agonism is revealed by the requirement of 20-fold higher concentration of GABA for detectable channel openings, a major population of brief openings, and absence of clusters of openings when compared with ACh. Mutations at key residues of the principal binding-site face of muscle nAChRs (aY190 and aG153) affect GABA activation similarly as ACh activation, whereas a mutation at the complementary face (EG57) shows a selective effect for GABA. Studies with subunit-lacking receptors show that GABA can activate muscle nAChRs through the a/d interface. Interestingly, single-channel activity elicited by GABA is similar to that elicited by ACh in gain-of-function nAChR mutants associated to congenital myasthenic syndromes, which could be important in the progression of the disorders due to steady exposure to serum GABA. In contrast, GABA cannot elicit single-channel or macroscopic currents of a7 or the chimeric a7-serotonin-type 3 receptor, a feature important for preserving an adequate excitatory/inhibitory balance in the brain as well as for avoiding activation of nonneuronal receptors by serum GABA.
Fil: Dionisio, Leonardo Raul. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
Fil: Bergé, Ignacio. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
Fil: Bravo, Matías. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
Fil: Esandi, María del Carmen. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnol.conicet - Bahia Blanca. Instituto de Invest.bioquimicas Bahia Blanca (i); Argentina
description Cys-loop receptors are neurotransmitter-activated ion channels involved in synaptic and extrasynaptic transmission in the brain and are also present in non-neuronal cells. As GABAA and nicotinic receptors (nAChR) belong to this family, we explored by macroscopic and single-channel recordings whether the inhibitory neurotransmitter GABA has the ability to activate excitatory nAChRs. GABA differentially activates nAChR subtypes. It activates muscle nAChRs, with maximal peak currents of about 10% of those elicited by acetylcholine (ACh) and 15- fold higher EC50 with respect to ACh. At the single-channel level, the weak agonism is revealed by the requirement of 20-fold higher concentration of GABA for detectable channel openings, a major population of brief openings, and absence of clusters of openings when compared with ACh. Mutations at key residues of the principal binding-site face of muscle nAChRs (aY190 and aG153) affect GABA activation similarly as ACh activation, whereas a mutation at the complementary face (EG57) shows a selective effect for GABA. Studies with subunit-lacking receptors show that GABA can activate muscle nAChRs through the a/d interface. Interestingly, single-channel activity elicited by GABA is similar to that elicited by ACh in gain-of-function nAChR mutants associated to congenital myasthenic syndromes, which could be important in the progression of the disorders due to steady exposure to serum GABA. In contrast, GABA cannot elicit single-channel or macroscopic currents of a7 or the chimeric a7-serotonin-type 3 receptor, a feature important for preserving an adequate excitatory/inhibitory balance in the brain as well as for avoiding activation of nonneuronal receptors by serum GABA.
publishDate 2015
dc.date.none.fl_str_mv 2015-03
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/11336/4378
Dionisio, Leonardo Raul; Bergé, Ignacio; Bravo, Matías; Esandi, María del Carmen; Bouzat, Cecilia Beatriz; Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors; American Society For Pharmacology And Experimental Therapeutics; Molecular Pharmacology; 87; 3-2015; 391-400
0026-895X
url http://hdl.handle.net/11336/4378
identifier_str_mv Dionisio, Leonardo Raul; Bergé, Ignacio; Bravo, Matías; Esandi, María del Carmen; Bouzat, Cecilia Beatriz; Neurotransmitter GABA Activates Muscle but not a7 Nicotinic Receptors; American Society For Pharmacology And Experimental Therapeutics; Molecular Pharmacology; 87; 3-2015; 391-400
0026-895X
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/ark/10.1124/mol.114.095539
info:eu-repo/semantics/altIdentifier/url/http://molpharm.aspetjournals.org/content/suppl/2014/12/09/mol.114.095539.DC1.html
info:eu-repo/semantics/altIdentifier/url/http://molpharm.aspetjournals.org/content/87/3/391.full.pdf
info:eu-repo/semantics/altIdentifier/doi/10.1124/mol.114.095539
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
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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