Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor

Autores
Lipovsek, Maria Marcela; Fierro, Angélica; Perez, Edwin G.; Boffi, Juan Carlos; Millar, Neil S.; Fuchs, Paul A.; Katz, Eleonora; Elgoyhen, Ana Belen
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Nicotinic acetylcholine receptors are a family of ligand-gated nonselective cationic channels that participate in fundamental physiological processes at both the central and the peripheral nervous system. The extent of calcium entry through ligand-gated ion channels defines their distinct functions. The α9α10 nicotinic cholinergic receptor, expressed in cochlear hair cells, is a peculiar member of the family as it shows differences in the extent of calcium permeability across species. In particular, mammalian α9α10 receptors are among the ligand-gated ion channels which exhibit the highest calcium selectivity. This acquired differential property provides the unique opportunity of studying how protein function was shaped along evolutionary history, by tracking its evolutionary record and experimentally defining the amino acid changes involved. We have applied a molecular evolution approach of ancestral sequence reconstruction, together with molecular dynamics simulations and an evolutionary-based mutagenesis strategy, in order to trace the molecular events that yielded a high calcium permeable nicotinic α9α10 mammalian receptor. Only three specific amino acid substitutions in the α9 subunit were directly involved. These are located at the extracellular vestibule and at the exit of the channel pore and not at the transmembrane region 2 of the protein as previously thought. Moreover, we show that these three critical substitutions only increase calcium permeability in the context of the mammalian but not the avian receptor, stressing the relevance of overall protein structure on defining functional properties. These results highlight the importance of tracking evolutionarily acquired changes in protein sequence underlying fundamental functional properties of ligand-gated ion channels.
Fil: Lipovsek, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Fierro, Angélica. Pontificia Universidad Católica de Chile; Chile
Fil: Perez, Edwin G.. Pontificia Universidad Católica de Chile; Chile
Fil: Boffi, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Millar, Neil S.. University College London; Estados Unidos
Fil: Fuchs, Paul A.. University Johns Hopkins; Estados Unidos
Fil: Katz, Eleonora. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Elgoyhen, Ana Belen. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Materia
Nicotinic Receptors
Calcium Permeability
Molecular Evolution
Hearing
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:11336/35966
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/35966
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine ReceptorLipovsek, Maria MarcelaFierro, AngélicaPerez, Edwin G.Boffi, Juan CarlosMillar, Neil S.Fuchs, Paul A.Katz, EleonoraElgoyhen, Ana BelenNicotinic ReceptorsCalcium PermeabilityMolecular EvolutionHearinghttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Nicotinic acetylcholine receptors are a family of ligand-gated nonselective cationic channels that participate in fundamental physiological processes at both the central and the peripheral nervous system. The extent of calcium entry through ligand-gated ion channels defines their distinct functions. The α9α10 nicotinic cholinergic receptor, expressed in cochlear hair cells, is a peculiar member of the family as it shows differences in the extent of calcium permeability across species. In particular, mammalian α9α10 receptors are among the ligand-gated ion channels which exhibit the highest calcium selectivity. This acquired differential property provides the unique opportunity of studying how protein function was shaped along evolutionary history, by tracking its evolutionary record and experimentally defining the amino acid changes involved. We have applied a molecular evolution approach of ancestral sequence reconstruction, together with molecular dynamics simulations and an evolutionary-based mutagenesis strategy, in order to trace the molecular events that yielded a high calcium permeable nicotinic α9α10 mammalian receptor. Only three specific amino acid substitutions in the α9 subunit were directly involved. These are located at the extracellular vestibule and at the exit of the channel pore and not at the transmembrane region 2 of the protein as previously thought. Moreover, we show that these three critical substitutions only increase calcium permeability in the context of the mammalian but not the avian receptor, stressing the relevance of overall protein structure on defining functional properties. These results highlight the importance of tracking evolutionarily acquired changes in protein sequence underlying fundamental functional properties of ligand-gated ion channels.Fil: Lipovsek, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; ArgentinaFil: Fierro, Angélica. Pontificia Universidad Católica de Chile; ChileFil: Perez, Edwin G.. Pontificia Universidad Católica de Chile; ChileFil: Boffi, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; ArgentinaFil: Millar, Neil S.. University College London; Estados UnidosFil: Fuchs, Paul A.. University Johns Hopkins; Estados UnidosFil: Katz, Eleonora. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; ArgentinaFil: Elgoyhen, Ana Belen. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; ArgentinaOxford University Press2014-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/35966Lipovsek, Maria Marcela; Fierro, Angélica ; Perez, Edwin G.; Boffi, Juan Carlos; Millar, Neil S. ; et al.; Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor; Oxford University Press; Molecular Biology and Evolution; 31; 12; 9-2014; 3250-32650737-4038CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1093/molbev/msu258info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/mbe/article/31/12/3250/2925689info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:43:30Zoai:ri.conicet.gov.ar:11336/35966instacron: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:34982025-10-15 14:43:30.844CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor
title Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor
spellingShingle Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor
Lipovsek, Maria Marcela
Nicotinic Receptors
Calcium Permeability
Molecular Evolution
Hearing
title_short Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor
title_full Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor
title_fullStr Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor
title_full_unstemmed Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor
title_sort Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor
dc.creator.none.fl_str_mv Lipovsek, Maria Marcela
Fierro, Angélica
Perez, Edwin G.
Boffi, Juan Carlos
Millar, Neil S.
Fuchs, Paul A.
Katz, Eleonora
Elgoyhen, Ana Belen
author Lipovsek, Maria Marcela
author_facet Lipovsek, Maria Marcela
Fierro, Angélica
Perez, Edwin G.
Boffi, Juan Carlos
Millar, Neil S.
Fuchs, Paul A.
Katz, Eleonora
Elgoyhen, Ana Belen
author_role author
author2 Fierro, Angélica
Perez, Edwin G.
Boffi, Juan Carlos
Millar, Neil S.
Fuchs, Paul A.
Katz, Eleonora
Elgoyhen, Ana Belen
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Nicotinic Receptors
Calcium Permeability
Molecular Evolution
Hearing
topic Nicotinic Receptors
Calcium Permeability
Molecular Evolution
Hearing
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 acetylcholine receptors are a family of ligand-gated nonselective cationic channels that participate in fundamental physiological processes at both the central and the peripheral nervous system. The extent of calcium entry through ligand-gated ion channels defines their distinct functions. The α9α10 nicotinic cholinergic receptor, expressed in cochlear hair cells, is a peculiar member of the family as it shows differences in the extent of calcium permeability across species. In particular, mammalian α9α10 receptors are among the ligand-gated ion channels which exhibit the highest calcium selectivity. This acquired differential property provides the unique opportunity of studying how protein function was shaped along evolutionary history, by tracking its evolutionary record and experimentally defining the amino acid changes involved. We have applied a molecular evolution approach of ancestral sequence reconstruction, together with molecular dynamics simulations and an evolutionary-based mutagenesis strategy, in order to trace the molecular events that yielded a high calcium permeable nicotinic α9α10 mammalian receptor. Only three specific amino acid substitutions in the α9 subunit were directly involved. These are located at the extracellular vestibule and at the exit of the channel pore and not at the transmembrane region 2 of the protein as previously thought. Moreover, we show that these three critical substitutions only increase calcium permeability in the context of the mammalian but not the avian receptor, stressing the relevance of overall protein structure on defining functional properties. These results highlight the importance of tracking evolutionarily acquired changes in protein sequence underlying fundamental functional properties of ligand-gated ion channels.
Fil: Lipovsek, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Fierro, Angélica. Pontificia Universidad Católica de Chile; Chile
Fil: Perez, Edwin G.. Pontificia Universidad Católica de Chile; Chile
Fil: Boffi, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Millar, Neil S.. University College London; Estados Unidos
Fil: Fuchs, Paul A.. University Johns Hopkins; Estados Unidos
Fil: Katz, Eleonora. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Elgoyhen, Ana Belen. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
description Nicotinic acetylcholine receptors are a family of ligand-gated nonselective cationic channels that participate in fundamental physiological processes at both the central and the peripheral nervous system. The extent of calcium entry through ligand-gated ion channels defines their distinct functions. The α9α10 nicotinic cholinergic receptor, expressed in cochlear hair cells, is a peculiar member of the family as it shows differences in the extent of calcium permeability across species. In particular, mammalian α9α10 receptors are among the ligand-gated ion channels which exhibit the highest calcium selectivity. This acquired differential property provides the unique opportunity of studying how protein function was shaped along evolutionary history, by tracking its evolutionary record and experimentally defining the amino acid changes involved. We have applied a molecular evolution approach of ancestral sequence reconstruction, together with molecular dynamics simulations and an evolutionary-based mutagenesis strategy, in order to trace the molecular events that yielded a high calcium permeable nicotinic α9α10 mammalian receptor. Only three specific amino acid substitutions in the α9 subunit were directly involved. These are located at the extracellular vestibule and at the exit of the channel pore and not at the transmembrane region 2 of the protein as previously thought. Moreover, we show that these three critical substitutions only increase calcium permeability in the context of the mammalian but not the avian receptor, stressing the relevance of overall protein structure on defining functional properties. These results highlight the importance of tracking evolutionarily acquired changes in protein sequence underlying fundamental functional properties of ligand-gated ion channels.
publishDate 2014
dc.date.none.fl_str_mv 2014-09
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/11336/35966
Lipovsek, Maria Marcela; Fierro, Angélica ; Perez, Edwin G.; Boffi, Juan Carlos; Millar, Neil S. ; et al.; Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor; Oxford University Press; Molecular Biology and Evolution; 31; 12; 9-2014; 3250-3265
0737-4038
CONICET Digital
CONICET
url http://hdl.handle.net/11336/35966
identifier_str_mv Lipovsek, Maria Marcela; Fierro, Angélica ; Perez, Edwin G.; Boffi, Juan Carlos; Millar, Neil S. ; et al.; Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor; Oxford University Press; Molecular Biology and Evolution; 31; 12; 9-2014; 3250-3265
0737-4038
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1093/molbev/msu258
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/mbe/article/31/12/3250/2925689
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
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford 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 13.22299

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