Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor

Autores
Pierce, Spencer R.; Germann, Allison L.; Xu, Sophia Q.; Menon, Saumith L.; Ortells, Marcelo Oscar; Arias, Hugo R.; Akk, Gustav
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The positive allosteric modulators (PAMs) of the α7 nicotinic receptor N-(5-Cl-2-hydroxyphenyl)-N′-[2-Cl-5-(trifluoromethyl)phenyl]-urea (NS-1738) and (E)-3-(furan-2-yl)-N-(p-tolyl)-acrylamide (PAM-2) potentiate the α1β2γ2L GABAA receptor through interactions with the classic anesthetic binding sites located at intersubunit interfaces in the transmembrane domain of the receptor. In the present study, we employed mutational analysis to investigate in detail the involvement and contributions made by the individual intersubunit interfaces to receptor modulation by NS-1738 and PAM-2. We show that mutations to each of the anesthetic-binding intersubunit interfaces (β+/α−, α+/β−, and γ+/β−), as well as the orphan α+/γ− interface, modify receptor potentiation by NS-1738 and PAM-2. Furthermore, mutations to any single interface can fully abolish potentiation by the α7-PAMs. The findings are discussed in the context of energetic additivity and interactions between the individual binding sites.
Fil: Pierce, Spencer R.. University of Washington. School of Medicine; Estados Unidos
Fil: Germann, Allison L.. University of Washington. School of Medicine; Estados Unidos
Fil: Xu, Sophia Q.. University of Washington. School of Medicine; Estados Unidos
Fil: Menon, Saumith L.. University of Washington. School of Medicine; Estados Unidos
Fil: Ortells, Marcelo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Morón; Argentina
Fil: Arias, Hugo R.. Oklahoma State University; Estados Unidos
Fil: Akk, Gustav. University of Washington. School of Medicine; Estados Unidos
Materia
ALLOSTERY
GABAA RECEPTOR
MODULATION
POTENTIATOR
Α7 NICOTINIC RECEPTOR
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/220215
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/220215
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic ReceptorPierce, Spencer R.Germann, Allison L.Xu, Sophia Q.Menon, Saumith L.Ortells, Marcelo OscarArias, Hugo R.Akk, GustavALLOSTERYGABAA RECEPTORMODULATIONPOTENTIATORΑ7 NICOTINIC RECEPTORhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The positive allosteric modulators (PAMs) of the α7 nicotinic receptor N-(5-Cl-2-hydroxyphenyl)-N′-[2-Cl-5-(trifluoromethyl)phenyl]-urea (NS-1738) and (E)-3-(furan-2-yl)-N-(p-tolyl)-acrylamide (PAM-2) potentiate the α1β2γ2L GABAA receptor through interactions with the classic anesthetic binding sites located at intersubunit interfaces in the transmembrane domain of the receptor. In the present study, we employed mutational analysis to investigate in detail the involvement and contributions made by the individual intersubunit interfaces to receptor modulation by NS-1738 and PAM-2. We show that mutations to each of the anesthetic-binding intersubunit interfaces (β+/α−, α+/β−, and γ+/β−), as well as the orphan α+/γ− interface, modify receptor potentiation by NS-1738 and PAM-2. Furthermore, mutations to any single interface can fully abolish potentiation by the α7-PAMs. The findings are discussed in the context of energetic additivity and interactions between the individual binding sites.Fil: Pierce, Spencer R.. University of Washington. School of Medicine; Estados UnidosFil: Germann, Allison L.. University of Washington. School of Medicine; Estados UnidosFil: Xu, Sophia Q.. University of Washington. School of Medicine; Estados UnidosFil: Menon, Saumith L.. University of Washington. School of Medicine; Estados UnidosFil: Ortells, Marcelo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Morón; ArgentinaFil: Arias, Hugo R.. Oklahoma State University; Estados UnidosFil: Akk, Gustav. University of Washington. School of Medicine; Estados UnidosMDPI2023-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/220215Pierce, Spencer R.; Germann, Allison L.; Xu, Sophia Q.; Menon, Saumith L.; Ortells, Marcelo Oscar; et al.; Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor; MDPI; Biomolecules; 13; 4; 4-2023; 1-192218-273XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/2218-273X/13/4/698info:eu-repo/semantics/altIdentifier/doi/10.3390/biom13040698info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:08:14Zoai:ri.conicet.gov.ar:11336/220215instacron: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 10:08:15.052CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor
title Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor
spellingShingle Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor
Pierce, Spencer R.
ALLOSTERY
GABAA RECEPTOR
MODULATION
POTENTIATOR
Α7 NICOTINIC RECEPTOR
title_short Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor
title_full Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor
title_fullStr Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor
title_full_unstemmed Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor
title_sort Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor
dc.creator.none.fl_str_mv Pierce, Spencer R.
Germann, Allison L.
Xu, Sophia Q.
Menon, Saumith L.
Ortells, Marcelo Oscar
Arias, Hugo R.
Akk, Gustav
author Pierce, Spencer R.
author_facet Pierce, Spencer R.
Germann, Allison L.
Xu, Sophia Q.
Menon, Saumith L.
Ortells, Marcelo Oscar
Arias, Hugo R.
Akk, Gustav
author_role author
author2 Germann, Allison L.
Xu, Sophia Q.
Menon, Saumith L.
Ortells, Marcelo Oscar
Arias, Hugo R.
Akk, Gustav
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv ALLOSTERY
GABAA RECEPTOR
MODULATION
POTENTIATOR
Α7 NICOTINIC RECEPTOR
topic ALLOSTERY
GABAA RECEPTOR
MODULATION
POTENTIATOR
Α7 NICOTINIC RECEPTOR
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The positive allosteric modulators (PAMs) of the α7 nicotinic receptor N-(5-Cl-2-hydroxyphenyl)-N′-[2-Cl-5-(trifluoromethyl)phenyl]-urea (NS-1738) and (E)-3-(furan-2-yl)-N-(p-tolyl)-acrylamide (PAM-2) potentiate the α1β2γ2L GABAA receptor through interactions with the classic anesthetic binding sites located at intersubunit interfaces in the transmembrane domain of the receptor. In the present study, we employed mutational analysis to investigate in detail the involvement and contributions made by the individual intersubunit interfaces to receptor modulation by NS-1738 and PAM-2. We show that mutations to each of the anesthetic-binding intersubunit interfaces (β+/α−, α+/β−, and γ+/β−), as well as the orphan α+/γ− interface, modify receptor potentiation by NS-1738 and PAM-2. Furthermore, mutations to any single interface can fully abolish potentiation by the α7-PAMs. The findings are discussed in the context of energetic additivity and interactions between the individual binding sites.
Fil: Pierce, Spencer R.. University of Washington. School of Medicine; Estados Unidos
Fil: Germann, Allison L.. University of Washington. School of Medicine; Estados Unidos
Fil: Xu, Sophia Q.. University of Washington. School of Medicine; Estados Unidos
Fil: Menon, Saumith L.. University of Washington. School of Medicine; Estados Unidos
Fil: Ortells, Marcelo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Morón; Argentina
Fil: Arias, Hugo R.. Oklahoma State University; Estados Unidos
Fil: Akk, Gustav. University of Washington. School of Medicine; Estados Unidos
description The positive allosteric modulators (PAMs) of the α7 nicotinic receptor N-(5-Cl-2-hydroxyphenyl)-N′-[2-Cl-5-(trifluoromethyl)phenyl]-urea (NS-1738) and (E)-3-(furan-2-yl)-N-(p-tolyl)-acrylamide (PAM-2) potentiate the α1β2γ2L GABAA receptor through interactions with the classic anesthetic binding sites located at intersubunit interfaces in the transmembrane domain of the receptor. In the present study, we employed mutational analysis to investigate in detail the involvement and contributions made by the individual intersubunit interfaces to receptor modulation by NS-1738 and PAM-2. We show that mutations to each of the anesthetic-binding intersubunit interfaces (β+/α−, α+/β−, and γ+/β−), as well as the orphan α+/γ− interface, modify receptor potentiation by NS-1738 and PAM-2. Furthermore, mutations to any single interface can fully abolish potentiation by the α7-PAMs. The findings are discussed in the context of energetic additivity and interactions between the individual binding sites.
publishDate 2023
dc.date.none.fl_str_mv 2023-04
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/11336/220215
Pierce, Spencer R.; Germann, Allison L.; Xu, Sophia Q.; Menon, Saumith L.; Ortells, Marcelo Oscar; et al.; Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor; MDPI; Biomolecules; 13; 4; 4-2023; 1-19
2218-273X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/220215
identifier_str_mv Pierce, Spencer R.; Germann, Allison L.; Xu, Sophia Q.; Menon, Saumith L.; Ortells, Marcelo Oscar; et al.; Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor; MDPI; Biomolecules; 13; 4; 4-2023; 1-19
2218-273X
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://www.mdpi.com/2218-273X/13/4/698
info:eu-repo/semantics/altIdentifier/doi/10.3390/biom13040698
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
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
_version_ 1842270037076869120
score 13.13397

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