A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries

Autores
Lasala, Matías Marcelo; Corradi, Jeremias; Bruzzone, Ariana; Esandi, María del Carmen; Bouzat, Cecilia Beatriz
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The cholinergic 7 nicotinic receptor gene, CHRNA7, encodes a subunit that forms the homopentameric 7 receptor, involved in learning and memory. In humans, exons 5–10 in CHRNA7 are duplicated and fused to the FAM7A genetic element, giving rise to the hybrid gene CHRFAM7A. Its product, dup7, is a truncated subunit lacking part of the N-terminal extracellular ligand-binding domain and is associated with neurological disorders, including schizophrenia, and immunomodulation. We combined dup7 expression on mammalian cells with patch clamp recordings to understand its functional role. Transfected cells expressed dup7 protein, but they exhibited neither surface binding of the 7 antagonist -bungaro-toxin nor responses to acetylcholine (ACh) or to an allosteric agonist that binds to the conserved transmembrane region. To determine whether dup7 assembles with 7, we generated receptors comprising 7 and dup7 subunits, one of which was tagged with conductance substitutions that report subunit stoichiometry and monitored ACh-elicited channel openings in the presence of a positive allosteric 7 modulator. We found that 7 and dup7 subunits co-assemble into functional heteromeric receptors, which require at least two 7 subunits for channel opening, and that dup7’s presence in the pentameric arrangement does not affect the duration of the potentiated events compared with that of 7. Using an 7 subunit mutant, we found that activation of (7) 2 (dup7) 3 receptors occurs through ACh binding at the 7/7 interfacial binding site. Our study contributes to the understanding of the modulation of 7 function by the human specific, duplicated subunit, associated with human disorders.
Fil: Lasala, Matías Marcelo. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Corradi, Jeremias. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Bruzzone, Ariana. 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: Esandi, María del Carmen. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Materia
NICOTINIC RECEPTORS
PATCH-CLAMP
CYS-LOOP
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:11336/85971
Acceder
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network_name_str CONICET Digital (CONICET)
spelling A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometriesLasala, Matías MarceloCorradi, JeremiasBruzzone, ArianaEsandi, María del CarmenBouzat, Cecilia BeatrizNICOTINIC RECEPTORSPATCH-CLAMPCYS-LOOPhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The cholinergic 7 nicotinic receptor gene, CHRNA7, encodes a subunit that forms the homopentameric 7 receptor, involved in learning and memory. In humans, exons 5–10 in CHRNA7 are duplicated and fused to the FAM7A genetic element, giving rise to the hybrid gene CHRFAM7A. Its product, dup7, is a truncated subunit lacking part of the N-terminal extracellular ligand-binding domain and is associated with neurological disorders, including schizophrenia, and immunomodulation. We combined dup7 expression on mammalian cells with patch clamp recordings to understand its functional role. Transfected cells expressed dup7 protein, but they exhibited neither surface binding of the 7 antagonist -bungaro-toxin nor responses to acetylcholine (ACh) or to an allosteric agonist that binds to the conserved transmembrane region. To determine whether dup7 assembles with 7, we generated receptors comprising 7 and dup7 subunits, one of which was tagged with conductance substitutions that report subunit stoichiometry and monitored ACh-elicited channel openings in the presence of a positive allosteric 7 modulator. We found that 7 and dup7 subunits co-assemble into functional heteromeric receptors, which require at least two 7 subunits for channel opening, and that dup7’s presence in the pentameric arrangement does not affect the duration of the potentiated events compared with that of 7. Using an 7 subunit mutant, we found that activation of (7) 2 (dup7) 3 receptors occurs through ACh binding at the 7/7 interfacial binding site. Our study contributes to the understanding of the modulation of 7 function by the human specific, duplicated subunit, associated with human disorders.Fil: Lasala, Matías Marcelo. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Corradi, Jeremias. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Bruzzone, Ariana. 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: Esandi, María del Carmen. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; 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; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaAmerican Society for Biochemistry and Molecular Biology2018-05-21info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/85971Lasala, Matías Marcelo; Corradi, Jeremias; Bruzzone, Ariana; Esandi, María del Carmen; Bouzat, Cecilia Beatriz; A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 293; 27; 21-5-2018; 10707-107170021-92581083-351XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/lookup/doi/10.1074/jbc.RA117.001698info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.RA117.001698info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:06:48Zoai:ri.conicet.gov.ar:11336/85971instacron: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 10:06:48.88CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries
title A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries
spellingShingle A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries
Lasala, Matías Marcelo
NICOTINIC RECEPTORS
PATCH-CLAMP
CYS-LOOP
title_short A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries
title_full A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries
title_fullStr A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries
title_full_unstemmed A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries
title_sort A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries
dc.creator.none.fl_str_mv Lasala, Matías Marcelo
Corradi, Jeremias
Bruzzone, Ariana
Esandi, María del Carmen
Bouzat, Cecilia Beatriz
author Lasala, Matías Marcelo
author_facet Lasala, Matías Marcelo
Corradi, Jeremias
Bruzzone, Ariana
Esandi, María del Carmen
Bouzat, Cecilia Beatriz
author_role author
author2 Corradi, Jeremias
Bruzzone, Ariana
Esandi, María del Carmen
Bouzat, Cecilia Beatriz
author2_role author
author
author
author
dc.subject.none.fl_str_mv NICOTINIC RECEPTORS
PATCH-CLAMP
CYS-LOOP
topic NICOTINIC RECEPTORS
PATCH-CLAMP
CYS-LOOP
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The cholinergic 7 nicotinic receptor gene, CHRNA7, encodes a subunit that forms the homopentameric 7 receptor, involved in learning and memory. In humans, exons 5–10 in CHRNA7 are duplicated and fused to the FAM7A genetic element, giving rise to the hybrid gene CHRFAM7A. Its product, dup7, is a truncated subunit lacking part of the N-terminal extracellular ligand-binding domain and is associated with neurological disorders, including schizophrenia, and immunomodulation. We combined dup7 expression on mammalian cells with patch clamp recordings to understand its functional role. Transfected cells expressed dup7 protein, but they exhibited neither surface binding of the 7 antagonist -bungaro-toxin nor responses to acetylcholine (ACh) or to an allosteric agonist that binds to the conserved transmembrane region. To determine whether dup7 assembles with 7, we generated receptors comprising 7 and dup7 subunits, one of which was tagged with conductance substitutions that report subunit stoichiometry and monitored ACh-elicited channel openings in the presence of a positive allosteric 7 modulator. We found that 7 and dup7 subunits co-assemble into functional heteromeric receptors, which require at least two 7 subunits for channel opening, and that dup7’s presence in the pentameric arrangement does not affect the duration of the potentiated events compared with that of 7. Using an 7 subunit mutant, we found that activation of (7) 2 (dup7) 3 receptors occurs through ACh binding at the 7/7 interfacial binding site. Our study contributes to the understanding of the modulation of 7 function by the human specific, duplicated subunit, associated with human disorders.
Fil: Lasala, Matías Marcelo. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Corradi, Jeremias. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Bruzzone, Ariana. 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: Esandi, María del Carmen. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
description The cholinergic 7 nicotinic receptor gene, CHRNA7, encodes a subunit that forms the homopentameric 7 receptor, involved in learning and memory. In humans, exons 5–10 in CHRNA7 are duplicated and fused to the FAM7A genetic element, giving rise to the hybrid gene CHRFAM7A. Its product, dup7, is a truncated subunit lacking part of the N-terminal extracellular ligand-binding domain and is associated with neurological disorders, including schizophrenia, and immunomodulation. We combined dup7 expression on mammalian cells with patch clamp recordings to understand its functional role. Transfected cells expressed dup7 protein, but they exhibited neither surface binding of the 7 antagonist -bungaro-toxin nor responses to acetylcholine (ACh) or to an allosteric agonist that binds to the conserved transmembrane region. To determine whether dup7 assembles with 7, we generated receptors comprising 7 and dup7 subunits, one of which was tagged with conductance substitutions that report subunit stoichiometry and monitored ACh-elicited channel openings in the presence of a positive allosteric 7 modulator. We found that 7 and dup7 subunits co-assemble into functional heteromeric receptors, which require at least two 7 subunits for channel opening, and that dup7’s presence in the pentameric arrangement does not affect the duration of the potentiated events compared with that of 7. Using an 7 subunit mutant, we found that activation of (7) 2 (dup7) 3 receptors occurs through ACh binding at the 7/7 interfacial binding site. Our study contributes to the understanding of the modulation of 7 function by the human specific, duplicated subunit, associated with human disorders.
publishDate 2018
dc.date.none.fl_str_mv 2018-05-21
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/11336/85971
Lasala, Matías Marcelo; Corradi, Jeremias; Bruzzone, Ariana; Esandi, María del Carmen; Bouzat, Cecilia Beatriz; A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 293; 27; 21-5-2018; 10707-10717
0021-9258
1083-351X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/85971
identifier_str_mv Lasala, Matías Marcelo; Corradi, Jeremias; Bruzzone, Ariana; Esandi, María del Carmen; Bouzat, Cecilia Beatriz; A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 293; 27; 21-5-2018; 10707-10717
0021-9258
1083-351X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/lookup/doi/10.1074/jbc.RA117.001698
info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.RA117.001698
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
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
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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score 13.13397

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