A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptor

Autores
Chrestia, Juan Facundo
Año de publicación
2021
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The binding of the viral spike protein (S) to angiotensin-converting enzyme 2 in host cells is crucial for infection. The S protein has been suggested to interact with nicotinic acetylcholine receptors (nAChRs), and their contribution to the COVID-19 inflammatory pathophysiology has been proposed. α7 is an interesting candidate target because it is present in neuronal and non-neuronal cells, and it has neuroprotective and anti-inflammatory actions. By whole-cell and single-channel recordings we revealed that the Y674-R685 region of the S protein shows a direct functional interaction with human α7 nAChR. The S fragment exerts a dual effect, acting as a low-efficacy agonist and a non-competitive antagonist. In agreement with molecular dynamics simulations showing stable binding of this region to the ACh binding pocket, the S fragment activates α7, but only in the presence of a potentiator, supporting its action as a very low-efficacy agonist. In addition, it allosterically inhibits α7 responses elicited by ACh, which may result in the predominant effect. This study provides unequivocal evidence supporting a functional α7-S protein interaction, which may play a role in infectivity and/or disease progression and may be explored for new therapeutic opportunities.
Fil: Chrestia, Juan Facundo. 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
XXXVI Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias
Buenos Aires
Argentina
Sociedad Argentina de Investigación en Neurociencias
Materia
NICOTINIC RECEPTOR
PATCH-CLAMP
SARS-CoV-2 SPIKE PROTEIN
SINGLE-CHANNEL RECORDINGS
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:11336/215795
Acceder
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network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptorChrestia, Juan FacundoNICOTINIC RECEPTORPATCH-CLAMPSARS-CoV-2 SPIKE PROTEINSINGLE-CHANNEL RECORDINGShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The binding of the viral spike protein (S) to angiotensin-converting enzyme 2 in host cells is crucial for infection. The S protein has been suggested to interact with nicotinic acetylcholine receptors (nAChRs), and their contribution to the COVID-19 inflammatory pathophysiology has been proposed. α7 is an interesting candidate target because it is present in neuronal and non-neuronal cells, and it has neuroprotective and anti-inflammatory actions. By whole-cell and single-channel recordings we revealed that the Y674-R685 region of the S protein shows a direct functional interaction with human α7 nAChR. The S fragment exerts a dual effect, acting as a low-efficacy agonist and a non-competitive antagonist. In agreement with molecular dynamics simulations showing stable binding of this region to the ACh binding pocket, the S fragment activates α7, but only in the presence of a potentiator, supporting its action as a very low-efficacy agonist. In addition, it allosterically inhibits α7 responses elicited by ACh, which may result in the predominant effect. This study provides unequivocal evidence supporting a functional α7-S protein interaction, which may play a role in infectivity and/or disease progression and may be explored for new therapeutic opportunities.Fil: Chrestia, Juan Facundo. 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; ArgentinaXXXVI Congreso Anual de la Sociedad Argentina de Investigación en NeurocienciasBuenos AiresArgentinaSociedad Argentina de Investigación en NeurocienciasSociedad Argentina de Investigación en Neurociencias2021info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/215795A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptor; XXXVI Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; Buenos Aires; Argentina; 2021; 47-47CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://saneurociencias.org.ar/Internacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:56:05Zoai:ri.conicet.gov.ar:11336/215795instacron: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 09:56:06.164CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptor
title A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptor
spellingShingle A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptor
Chrestia, Juan Facundo
NICOTINIC RECEPTOR
PATCH-CLAMP
SARS-CoV-2 SPIKE PROTEIN
SINGLE-CHANNEL RECORDINGS
title_short A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptor
title_full A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptor
title_fullStr A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptor
title_full_unstemmed A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptor
title_sort A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptor
dc.creator.none.fl_str_mv Chrestia, Juan Facundo
author Chrestia, Juan Facundo
author_facet Chrestia, Juan Facundo
author_role author
dc.subject.none.fl_str_mv NICOTINIC RECEPTOR
PATCH-CLAMP
SARS-CoV-2 SPIKE PROTEIN
SINGLE-CHANNEL RECORDINGS
topic NICOTINIC RECEPTOR
PATCH-CLAMP
SARS-CoV-2 SPIKE PROTEIN
SINGLE-CHANNEL RECORDINGS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The binding of the viral spike protein (S) to angiotensin-converting enzyme 2 in host cells is crucial for infection. The S protein has been suggested to interact with nicotinic acetylcholine receptors (nAChRs), and their contribution to the COVID-19 inflammatory pathophysiology has been proposed. α7 is an interesting candidate target because it is present in neuronal and non-neuronal cells, and it has neuroprotective and anti-inflammatory actions. By whole-cell and single-channel recordings we revealed that the Y674-R685 region of the S protein shows a direct functional interaction with human α7 nAChR. The S fragment exerts a dual effect, acting as a low-efficacy agonist and a non-competitive antagonist. In agreement with molecular dynamics simulations showing stable binding of this region to the ACh binding pocket, the S fragment activates α7, but only in the presence of a potentiator, supporting its action as a very low-efficacy agonist. In addition, it allosterically inhibits α7 responses elicited by ACh, which may result in the predominant effect. This study provides unequivocal evidence supporting a functional α7-S protein interaction, which may play a role in infectivity and/or disease progression and may be explored for new therapeutic opportunities.
Fil: Chrestia, Juan Facundo. 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
XXXVI Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias
Buenos Aires
Argentina
Sociedad Argentina de Investigación en Neurociencias
description Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The binding of the viral spike protein (S) to angiotensin-converting enzyme 2 in host cells is crucial for infection. The S protein has been suggested to interact with nicotinic acetylcholine receptors (nAChRs), and their contribution to the COVID-19 inflammatory pathophysiology has been proposed. α7 is an interesting candidate target because it is present in neuronal and non-neuronal cells, and it has neuroprotective and anti-inflammatory actions. By whole-cell and single-channel recordings we revealed that the Y674-R685 region of the S protein shows a direct functional interaction with human α7 nAChR. The S fragment exerts a dual effect, acting as a low-efficacy agonist and a non-competitive antagonist. In agreement with molecular dynamics simulations showing stable binding of this region to the ACh binding pocket, the S fragment activates α7, but only in the presence of a potentiator, supporting its action as a very low-efficacy agonist. In addition, it allosterically inhibits α7 responses elicited by ACh, which may result in the predominant effect. This study provides unequivocal evidence supporting a functional α7-S protein interaction, which may play a role in infectivity and/or disease progression and may be explored for new therapeutic opportunities.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Congreso
Journal
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/215795
A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptor; XXXVI Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; Buenos Aires; Argentina; 2021; 47-47
CONICET Digital
CONICET
url http://hdl.handle.net/11336/215795
identifier_str_mv A functional interaction between a region of the SARS-CoV-2 spike protein and the human α7 nicotinic receptor; XXXVI Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; Buenos Aires; Argentina; 2021; 47-47
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://saneurociencias.org.ar/
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.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Sociedad Argentina de Investigación en Neurociencias
publisher.none.fl_str_mv Sociedad Argentina de Investigación en Neurociencias
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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