Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor

Autores
Natarajan, Kathiresan; Mukhtasimova, Nuriya; Corradi, Jeremias; Lasala, Matías Marcelo; Bouzat, Cecilia Beatriz; Sine, Steven M.
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The α7 nicotinic acetylcholine receptor (nAChR) is among the most abundant types of nAChR in the brain, yet the ability of nerve-released ACh to activate α7 remains enigmatic. In particular, a major population of α7 resides in extra-synaptic regions where the ACh concentration is reduced, owing to dilution and enzymatic hydrolysis, yet ACh shows low potency in activating α7. Using high-resolution single-channel recording techniques, we show that extracellular calcium is a powerful potentiator of α7 activated by low concentrations of ACh. Potentiation manifests as robust increases in the frequency of channel opening and the average duration of the openings. Molecular dynamics simulations reveal that calcium binds to the periphery of the five ligand binding sites and is framed by a pair of anionic residues from the principal and complementary faces of each site. Mutation of residues identified by simulation prevents calcium from potentiating ACh-elicited channel opening. An anionic residue is conserved at each of the identified positions in all vertebrate species of α7. Thus, calcium associates with a novel structural motif on α7 and is an obligate cofactor in regions of limited ACh concentration.
Fil: Natarajan, Kathiresan. Mayo Clinic Cancer Center; Estados Unidos
Fil: Mukhtasimova, Nuriya. Mayo Clinic Cancer Center; Estados Unidos
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: 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: 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
Fil: Sine, Steven M.. Mayo Clinic Cancer Center; Estados Unidos
Materia
PATCH-CLAMP
MODULATION
NICOTINIC
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acceso embargado
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
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CONICET Digital (CONICET)
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Consejo Nacional de Investigaciones Científicas y Técnicas
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oai:ri.conicet.gov.ar:11336/111352
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptorNatarajan, KathiresanMukhtasimova, NuriyaCorradi, JeremiasLasala, Matías MarceloBouzat, Cecilia BeatrizSine, Steven M.PATCH-CLAMPMODULATIONNICOTINIChttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The α7 nicotinic acetylcholine receptor (nAChR) is among the most abundant types of nAChR in the brain, yet the ability of nerve-released ACh to activate α7 remains enigmatic. In particular, a major population of α7 resides in extra-synaptic regions where the ACh concentration is reduced, owing to dilution and enzymatic hydrolysis, yet ACh shows low potency in activating α7. Using high-resolution single-channel recording techniques, we show that extracellular calcium is a powerful potentiator of α7 activated by low concentrations of ACh. Potentiation manifests as robust increases in the frequency of channel opening and the average duration of the openings. Molecular dynamics simulations reveal that calcium binds to the periphery of the five ligand binding sites and is framed by a pair of anionic residues from the principal and complementary faces of each site. Mutation of residues identified by simulation prevents calcium from potentiating ACh-elicited channel opening. An anionic residue is conserved at each of the identified positions in all vertebrate species of α7. Thus, calcium associates with a novel structural motif on α7 and is an obligate cofactor in regions of limited ACh concentration.Fil: Natarajan, Kathiresan. Mayo Clinic Cancer Center; Estados UnidosFil: Mukhtasimova, Nuriya. Mayo Clinic Cancer Center; Estados UnidosFil: 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: 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: 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; ArgentinaFil: Sine, Steven M.. Mayo Clinic Cancer Center; Estados UnidosRockefeller University Press2020-07-23info:eu-repo/date/embargoEnd/2021-01-23info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/111352Natarajan, Kathiresan; Mukhtasimova, Nuriya; Corradi, Jeremias; Lasala, Matías Marcelo; Bouzat, Cecilia Beatriz; et al.; Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor; Rockefeller University Press; Journal Of General Physiology; 152; 9; 23-7-2020; 1-230022-12951540-7748CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://rupress.org/jgp/article/152/9/e202012606/151971/Mechanism-of-calcium-potentiation-of-the-7info:eu-repo/semantics/altIdentifier/doi/10.1085/jgp.202012606info:eu-repo/semantics/embargoedAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:47:01Zoai:ri.conicet.gov.ar:11336/111352instacron: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 09:47:01.308CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor
title Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor
spellingShingle Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor
Natarajan, Kathiresan
PATCH-CLAMP
MODULATION
NICOTINIC
title_short Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor
title_full Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor
title_fullStr Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor
title_full_unstemmed Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor
title_sort Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor
dc.creator.none.fl_str_mv Natarajan, Kathiresan
Mukhtasimova, Nuriya
Corradi, Jeremias
Lasala, Matías Marcelo
Bouzat, Cecilia Beatriz
Sine, Steven M.
author Natarajan, Kathiresan
author_facet Natarajan, Kathiresan
Mukhtasimova, Nuriya
Corradi, Jeremias
Lasala, Matías Marcelo
Bouzat, Cecilia Beatriz
Sine, Steven M.
author_role author
author2 Mukhtasimova, Nuriya
Corradi, Jeremias
Lasala, Matías Marcelo
Bouzat, Cecilia Beatriz
Sine, Steven M.
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv PATCH-CLAMP
MODULATION
NICOTINIC
topic PATCH-CLAMP
MODULATION
NICOTINIC
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 α7 nicotinic acetylcholine receptor (nAChR) is among the most abundant types of nAChR in the brain, yet the ability of nerve-released ACh to activate α7 remains enigmatic. In particular, a major population of α7 resides in extra-synaptic regions where the ACh concentration is reduced, owing to dilution and enzymatic hydrolysis, yet ACh shows low potency in activating α7. Using high-resolution single-channel recording techniques, we show that extracellular calcium is a powerful potentiator of α7 activated by low concentrations of ACh. Potentiation manifests as robust increases in the frequency of channel opening and the average duration of the openings. Molecular dynamics simulations reveal that calcium binds to the periphery of the five ligand binding sites and is framed by a pair of anionic residues from the principal and complementary faces of each site. Mutation of residues identified by simulation prevents calcium from potentiating ACh-elicited channel opening. An anionic residue is conserved at each of the identified positions in all vertebrate species of α7. Thus, calcium associates with a novel structural motif on α7 and is an obligate cofactor in regions of limited ACh concentration.
Fil: Natarajan, Kathiresan. Mayo Clinic Cancer Center; Estados Unidos
Fil: Mukhtasimova, Nuriya. Mayo Clinic Cancer Center; Estados Unidos
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: 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: 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
Fil: Sine, Steven M.. Mayo Clinic Cancer Center; Estados Unidos
description The α7 nicotinic acetylcholine receptor (nAChR) is among the most abundant types of nAChR in the brain, yet the ability of nerve-released ACh to activate α7 remains enigmatic. In particular, a major population of α7 resides in extra-synaptic regions where the ACh concentration is reduced, owing to dilution and enzymatic hydrolysis, yet ACh shows low potency in activating α7. Using high-resolution single-channel recording techniques, we show that extracellular calcium is a powerful potentiator of α7 activated by low concentrations of ACh. Potentiation manifests as robust increases in the frequency of channel opening and the average duration of the openings. Molecular dynamics simulations reveal that calcium binds to the periphery of the five ligand binding sites and is framed by a pair of anionic residues from the principal and complementary faces of each site. Mutation of residues identified by simulation prevents calcium from potentiating ACh-elicited channel opening. An anionic residue is conserved at each of the identified positions in all vertebrate species of α7. Thus, calcium associates with a novel structural motif on α7 and is an obligate cofactor in regions of limited ACh concentration.
publishDate 2020
dc.date.none.fl_str_mv 2020-07-23
info:eu-repo/date/embargoEnd/2021-01-23
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/11336/111352
Natarajan, Kathiresan; Mukhtasimova, Nuriya; Corradi, Jeremias; Lasala, Matías Marcelo; Bouzat, Cecilia Beatriz; et al.; Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor; Rockefeller University Press; Journal Of General Physiology; 152; 9; 23-7-2020; 1-23
0022-1295
1540-7748
CONICET Digital
CONICET
url http://hdl.handle.net/11336/111352
identifier_str_mv Natarajan, Kathiresan; Mukhtasimova, Nuriya; Corradi, Jeremias; Lasala, Matías Marcelo; Bouzat, Cecilia Beatriz; et al.; Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor; Rockefeller University Press; Journal Of General Physiology; 152; 9; 23-7-2020; 1-23
0022-1295
1540-7748
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://rupress.org/jgp/article/152/9/e202012606/151971/Mechanism-of-calcium-potentiation-of-the-7
info:eu-repo/semantics/altIdentifier/doi/10.1085/jgp.202012606
dc.rights.none.fl_str_mv info:eu-repo/semantics/embargoedAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv embargoedAccess
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 Rockefeller University Press
publisher.none.fl_str_mv Rockefeller University Press
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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