Searching for the Cannabidiol Binding Site on the α7 Nicotinic Acetylcholine Receptor

Autores
Chrestia, Juan Facundo; Viscarra, Franco; Bermúdez, Isabel; Bouzat, Cecilia Beatriz
Año de publicación
2024
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
The α7 nicotinic receptor is an acetylcholine-gated ion channel found in both neuronal and non-neuronal cells. Reduced α7 activity is associated with neurological and neurodegenerative disorders, whereas increased α7 activity may promote cancer progression. Therefore, both potentiation and inhibition of the receptor are of therapeutic interest. Cannabidiol (CBD), widely used for its therapeutic benefits and lack of psychoactive effects, is a known modulator of α7. Using patch-clamp recordings, we showed that CBD exerts two distinct modulatory effects on α7, each occurring at different time scales: a rapid reduction in the frequency of activation episodes, followed by a delayed effect characterized by prolonged activation episodes after several minutes. To predict CBD’s binding sites, we employed molecular dynamics simulations of α7 in both resting and desensitized states, embedded in a POPC:POPA:CHOL membrane with CBD molecules. Several candidate binding sites emerged for each receptor state. Representative structures were then backmapped to atomistic detail and further simulated to explore the stability and interactions at each site. In both states, the most stable binding site was located near the top of the transmembrane domain. Contact analysis identified multiple residues of interest for mutagenesis. Electrophysiological recordings of mutant receptors, compared to wild-type, displayed altered sensitivity to CBD’s effects, with some mutants showing reduced sensitivity to the immediate inhibitory effect, while others were more responsive to the kinetic changes. These findings confirm the role of specific residues in the allosteric modulation of α7 by CBD, with different residues contributing to its distinct effects on receptor function
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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Viscarra, Franco. Oxford Brookes University (oxford Brookes University);
Fil: Bermúdez, Isabel. Oxford Brookes University (oxford Brookes University);
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
LII Reunión Anual de la Sociedad Argentina de Biofísica
Bahía Blanca
Argentina
Sociedad Argentina de Biofísica
Universidad Nacional del Sur
Materia
ALPHA 7 NICOTINIC RECEPTOR
MOLECULAR DYNAMIC SIMULATION
CANNABIDIOL
PATCH-CLAMP
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/289765
Acceder
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Searching for the Cannabidiol Binding Site on the α7 Nicotinic Acetylcholine ReceptorChrestia, Juan FacundoViscarra, FrancoBermúdez, IsabelBouzat, Cecilia BeatrizALPHA 7 NICOTINIC RECEPTORMOLECULAR DYNAMIC SIMULATIONCANNABIDIOLPATCH-CLAMPhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The α7 nicotinic receptor is an acetylcholine-gated ion channel found in both neuronal and non-neuronal cells. Reduced α7 activity is associated with neurological and neurodegenerative disorders, whereas increased α7 activity may promote cancer progression. Therefore, both potentiation and inhibition of the receptor are of therapeutic interest. Cannabidiol (CBD), widely used for its therapeutic benefits and lack of psychoactive effects, is a known modulator of α7. Using patch-clamp recordings, we showed that CBD exerts two distinct modulatory effects on α7, each occurring at different time scales: a rapid reduction in the frequency of activation episodes, followed by a delayed effect characterized by prolonged activation episodes after several minutes. To predict CBD’s binding sites, we employed molecular dynamics simulations of α7 in both resting and desensitized states, embedded in a POPC:POPA:CHOL membrane with CBD molecules. Several candidate binding sites emerged for each receptor state. Representative structures were then backmapped to atomistic detail and further simulated to explore the stability and interactions at each site. In both states, the most stable binding site was located near the top of the transmembrane domain. Contact analysis identified multiple residues of interest for mutagenesis. Electrophysiological recordings of mutant receptors, compared to wild-type, displayed altered sensitivity to CBD’s effects, with some mutants showing reduced sensitivity to the immediate inhibitory effect, while others were more responsive to the kinetic changes. These findings confirm the role of specific residues in the allosteric modulation of α7 by CBD, with different residues contributing to its distinct effects on receptor functionFil: 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Viscarra, Franco. Oxford Brookes University (oxford Brookes University);Fil: Bermúdez, Isabel. Oxford Brookes University (oxford Brookes University);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; ArgentinaLII Reunión Anual de la Sociedad Argentina de BiofísicaBahía BlancaArgentinaSociedad Argentina de BiofísicaUniversidad Nacional del SurSociedad Argentina de BiofísicaAcierno, Juan PabloCelej, Maria SoledadVázquez, Diego EduardoRivas, Gabriela Leonor2024info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/289765Searching for the Cannabidiol Binding Site on the α7 Nicotinic Acetylcholine Receptor; LII Reunión Anual de la Sociedad Argentina de Biofísica; Bahía Blanca; Argentina; 2024; 62-62CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/congreso-2024/#resumenesInternacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T14:45:48Zoai:ri.conicet.gov.ar:11336/289765instacron: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:34982026-08-25 14:45:48.319CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Searching for the Cannabidiol Binding Site on the α7 Nicotinic Acetylcholine Receptor
title Searching for the Cannabidiol Binding Site on the α7 Nicotinic Acetylcholine Receptor
spellingShingle Searching for the Cannabidiol Binding Site on the α7 Nicotinic Acetylcholine Receptor
Chrestia, Juan Facundo
ALPHA 7 NICOTINIC RECEPTOR
MOLECULAR DYNAMIC SIMULATION
CANNABIDIOL
PATCH-CLAMP
title_short Searching for the Cannabidiol Binding Site on the α7 Nicotinic Acetylcholine Receptor
title_full Searching for the Cannabidiol Binding Site on the α7 Nicotinic Acetylcholine Receptor
title_fullStr Searching for the Cannabidiol Binding Site on the α7 Nicotinic Acetylcholine Receptor
title_full_unstemmed Searching for the Cannabidiol Binding Site on the α7 Nicotinic Acetylcholine Receptor
title_sort Searching for the Cannabidiol Binding Site on the α7 Nicotinic Acetylcholine Receptor
dc.creator.none.fl_str_mv Chrestia, Juan Facundo
Viscarra, Franco
Bermúdez, Isabel
Bouzat, Cecilia Beatriz
author Chrestia, Juan Facundo
author_facet Chrestia, Juan Facundo
Viscarra, Franco
Bermúdez, Isabel
Bouzat, Cecilia Beatriz
author_role author
author2 Viscarra, Franco
Bermúdez, Isabel
Bouzat, Cecilia Beatriz
author2_role author
author
author
dc.contributor.none.fl_str_mv Acierno, Juan Pablo
Celej, Maria Soledad
Vázquez, Diego Eduardo
Rivas, Gabriela Leonor
dc.subject.none.fl_str_mv ALPHA 7 NICOTINIC RECEPTOR
MOLECULAR DYNAMIC SIMULATION
CANNABIDIOL
PATCH-CLAMP
topic ALPHA 7 NICOTINIC RECEPTOR
MOLECULAR DYNAMIC SIMULATION
CANNABIDIOL
PATCH-CLAMP
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 receptor is an acetylcholine-gated ion channel found in both neuronal and non-neuronal cells. Reduced α7 activity is associated with neurological and neurodegenerative disorders, whereas increased α7 activity may promote cancer progression. Therefore, both potentiation and inhibition of the receptor are of therapeutic interest. Cannabidiol (CBD), widely used for its therapeutic benefits and lack of psychoactive effects, is a known modulator of α7. Using patch-clamp recordings, we showed that CBD exerts two distinct modulatory effects on α7, each occurring at different time scales: a rapid reduction in the frequency of activation episodes, followed by a delayed effect characterized by prolonged activation episodes after several minutes. To predict CBD’s binding sites, we employed molecular dynamics simulations of α7 in both resting and desensitized states, embedded in a POPC:POPA:CHOL membrane with CBD molecules. Several candidate binding sites emerged for each receptor state. Representative structures were then backmapped to atomistic detail and further simulated to explore the stability and interactions at each site. In both states, the most stable binding site was located near the top of the transmembrane domain. Contact analysis identified multiple residues of interest for mutagenesis. Electrophysiological recordings of mutant receptors, compared to wild-type, displayed altered sensitivity to CBD’s effects, with some mutants showing reduced sensitivity to the immediate inhibitory effect, while others were more responsive to the kinetic changes. These findings confirm the role of specific residues in the allosteric modulation of α7 by CBD, with different residues contributing to its distinct effects on receptor function
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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Viscarra, Franco. Oxford Brookes University (oxford Brookes University);
Fil: Bermúdez, Isabel. Oxford Brookes University (oxford Brookes University);
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
LII Reunión Anual de la Sociedad Argentina de Biofísica
Bahía Blanca
Argentina
Sociedad Argentina de Biofísica
Universidad Nacional del Sur
description The α7 nicotinic receptor is an acetylcholine-gated ion channel found in both neuronal and non-neuronal cells. Reduced α7 activity is associated with neurological and neurodegenerative disorders, whereas increased α7 activity may promote cancer progression. Therefore, both potentiation and inhibition of the receptor are of therapeutic interest. Cannabidiol (CBD), widely used for its therapeutic benefits and lack of psychoactive effects, is a known modulator of α7. Using patch-clamp recordings, we showed that CBD exerts two distinct modulatory effects on α7, each occurring at different time scales: a rapid reduction in the frequency of activation episodes, followed by a delayed effect characterized by prolonged activation episodes after several minutes. To predict CBD’s binding sites, we employed molecular dynamics simulations of α7 in both resting and desensitized states, embedded in a POPC:POPA:CHOL membrane with CBD molecules. Several candidate binding sites emerged for each receptor state. Representative structures were then backmapped to atomistic detail and further simulated to explore the stability and interactions at each site. In both states, the most stable binding site was located near the top of the transmembrane domain. Contact analysis identified multiple residues of interest for mutagenesis. Electrophysiological recordings of mutant receptors, compared to wild-type, displayed altered sensitivity to CBD’s effects, with some mutants showing reduced sensitivity to the immediate inhibitory effect, while others were more responsive to the kinetic changes. These findings confirm the role of specific residues in the allosteric modulation of α7 by CBD, with different residues contributing to its distinct effects on receptor function
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Congreso
Book
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/11336/289765
Searching for the Cannabidiol Binding Site on the α7 Nicotinic Acetylcholine Receptor; LII Reunión Anual de la Sociedad Argentina de Biofísica; Bahía Blanca; Argentina; 2024; 62-62
CONICET Digital
CONICET
url http://hdl.handle.net/11336/289765
identifier_str_mv Searching for the Cannabidiol Binding Site on the α7 Nicotinic Acetylcholine Receptor; LII Reunión Anual de la Sociedad Argentina de Biofísica; Bahía Blanca; Argentina; 2024; 62-62
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://biofisica.org.ar/congreso-2024/#resumenes
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Sociedad Argentina de Biofísica
publisher.none.fl_str_mv Sociedad Argentina de Biofísica
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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