Identification of a Cannabidiol Binding Domain Involved in the Allosteric Modulation of the alpha7 Nicotinic Acetylcholine Receptor

Autores
Chrestia, Juan Facundo; Viscarra, Franco; Bermúdez, Isabel; Bouzat, Cecilia
Año de publicación
2025
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
The α7 nicotinic acetylcholine receptor is a homopentameric ligand-gated ion channel widely expressed in the brain and also present in non-neuronal cells. It contributes to cognition, memory, neuroprotection, and the control of inflammation. Reduced α7 activity has been associated with neurological and neurodegenerative disorders, whereas enhanced activity may promote cancer progression. Thus, both potentiation and inhibition of α7 are of therapeutic interest. Cannabidiol (CBD), a non-psychoactive compound with therapeutic potential and broad use, is an α7 modulator. Using patch- clamp recordings, we found that CBD rapidly decreases the frequency of α7 activation episodes while also inducing delayed, prolonged openings, suggesting multiple binding sites or mechanisms. To predict binding sites, we performed coarse-grained molecular dynamics simulations of α7 in resting and desensitized states embedded in a POPC:POPA:CHOL membrane in the presence of CBD. Several potential sites were identified. Representative structures were backmapped to atomistic detail and simulated to analyze stability and interactions. In the desensitized state, two residues from M4 interacted with CBD, while two others from M1 contributed to the resting site. Furthermore, one residue from the Cys-loop was involved in both states. These residues define a putative CBD binding domain located at the extracellular-facing apex of the M1 and M4 helices. To test their functional contribution, residues were mutated to alanine and electrophysiological recordings were performed. Mutants displayed altered responses to CBD: some mutations primarily reduced sensitivity to inhibition by affecting opening frequency, whereas others prolonged activation episodes by modifying channel kinetics. These effects did not segregate strictly by site, as residues from different locations showed overlapping functional roles. Taken together, our results support the existence of a CBD binding domain that allosterically modulates α7. Understanding these mechanisms is crucial for the rational therapeutic use of CBD and for anticipating possible adverse effects.
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. 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
LIII Reunión Anual de la Sociedad Argentina de Biofísica
Buenos Aires
Argentina
Sociedad Argentina de Biofísica
Universidad Nacional de Buenos Aires
Materia
ALPHA 7 NICOTINIC RECEPTOR
CANNABIDIOL
MOLECULAR DYNAMIC SIMULATION
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:11336/289823
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/289823
network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Identification of a Cannabidiol Binding Domain Involved in the Allosteric Modulation of the alpha7 Nicotinic Acetylcholine ReceptorChrestia, Juan FacundoViscarra, FrancoBermúdez, IsabelBouzat, CeciliaALPHA 7 NICOTINIC RECEPTORCANNABIDIOLMOLECULAR DYNAMIC SIMULATIONPATCH-CLAMPhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The α7 nicotinic acetylcholine receptor is a homopentameric ligand-gated ion channel widely expressed in the brain and also present in non-neuronal cells. It contributes to cognition, memory, neuroprotection, and the control of inflammation. Reduced α7 activity has been associated with neurological and neurodegenerative disorders, whereas enhanced activity may promote cancer progression. Thus, both potentiation and inhibition of α7 are of therapeutic interest. Cannabidiol (CBD), a non-psychoactive compound with therapeutic potential and broad use, is an α7 modulator. Using patch- clamp recordings, we found that CBD rapidly decreases the frequency of α7 activation episodes while also inducing delayed, prolonged openings, suggesting multiple binding sites or mechanisms. To predict binding sites, we performed coarse-grained molecular dynamics simulations of α7 in resting and desensitized states embedded in a POPC:POPA:CHOL membrane in the presence of CBD. Several potential sites were identified. Representative structures were backmapped to atomistic detail and simulated to analyze stability and interactions. In the desensitized state, two residues from M4 interacted with CBD, while two others from M1 contributed to the resting site. Furthermore, one residue from the Cys-loop was involved in both states. These residues define a putative CBD binding domain located at the extracellular-facing apex of the M1 and M4 helices. To test their functional contribution, residues were mutated to alanine and electrophysiological recordings were performed. Mutants displayed altered responses to CBD: some mutations primarily reduced sensitivity to inhibition by affecting opening frequency, whereas others prolonged activation episodes by modifying channel kinetics. These effects did not segregate strictly by site, as residues from different locations showed overlapping functional roles. Taken together, our results support the existence of a CBD binding domain that allosterically modulates α7. Understanding these mechanisms is crucial for the rational therapeutic use of CBD and for anticipating possible adverse effects.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; ArgentinaFil: Viscarra, Franco. Oxford Brookes University (oxford Brookes University);Fil: Bermúdez, Isabel. Oxford Brookes University (oxford Brookes University);Fil: Bouzat, Cecilia. 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; ArgentinaLIII Reunión Anual de la Sociedad Argentina de BiofísicaBuenos AiresArgentinaSociedad Argentina de BiofísicaUniversidad Nacional de Buenos AiresSociedad Argentina de BiofísicaVázquez, Diego EduardoDi Lella, Santiago2025info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/289823Identification of a Cannabidiol Binding Domain Involved in the Allosteric Modulation of the alpha7 Nicotinic Acetylcholine Receptor; LIII Reunión Anual de la Sociedad Argentina de Biofísica; Buenos Aires; Argentina; 2025; 86-86978-987-48938-3-3CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/congreso-2025/#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 Técnicas2026-08-25T15:28:33Zoai:ri.conicet.gov.ar:11336/289823instacron: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 15:28:34.275CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Identification of a Cannabidiol Binding Domain Involved in the Allosteric Modulation of the alpha7 Nicotinic Acetylcholine Receptor
title Identification of a Cannabidiol Binding Domain Involved in the Allosteric Modulation of the alpha7 Nicotinic Acetylcholine Receptor
spellingShingle Identification of a Cannabidiol Binding Domain Involved in the Allosteric Modulation of the alpha7 Nicotinic Acetylcholine Receptor
Chrestia, Juan Facundo
ALPHA 7 NICOTINIC RECEPTOR
CANNABIDIOL
MOLECULAR DYNAMIC SIMULATION
PATCH-CLAMP
title_short Identification of a Cannabidiol Binding Domain Involved in the Allosteric Modulation of the alpha7 Nicotinic Acetylcholine Receptor
title_full Identification of a Cannabidiol Binding Domain Involved in the Allosteric Modulation of the alpha7 Nicotinic Acetylcholine Receptor
title_fullStr Identification of a Cannabidiol Binding Domain Involved in the Allosteric Modulation of the alpha7 Nicotinic Acetylcholine Receptor
title_full_unstemmed Identification of a Cannabidiol Binding Domain Involved in the Allosteric Modulation of the alpha7 Nicotinic Acetylcholine Receptor
title_sort Identification of a Cannabidiol Binding Domain Involved in the Allosteric Modulation of the alpha7 Nicotinic Acetylcholine Receptor
dc.creator.none.fl_str_mv Chrestia, Juan Facundo
Viscarra, Franco
Bermúdez, Isabel
Bouzat, Cecilia
author Chrestia, Juan Facundo
author_facet Chrestia, Juan Facundo
Viscarra, Franco
Bermúdez, Isabel
Bouzat, Cecilia
author_role author
author2 Viscarra, Franco
Bermúdez, Isabel
Bouzat, Cecilia
author2_role author
author
author
dc.contributor.none.fl_str_mv Vázquez, Diego Eduardo
Di Lella, Santiago
dc.subject.none.fl_str_mv ALPHA 7 NICOTINIC RECEPTOR
CANNABIDIOL
MOLECULAR DYNAMIC SIMULATION
PATCH-CLAMP
topic ALPHA 7 NICOTINIC RECEPTOR
CANNABIDIOL
MOLECULAR DYNAMIC SIMULATION
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 acetylcholine receptor is a homopentameric ligand-gated ion channel widely expressed in the brain and also present in non-neuronal cells. It contributes to cognition, memory, neuroprotection, and the control of inflammation. Reduced α7 activity has been associated with neurological and neurodegenerative disorders, whereas enhanced activity may promote cancer progression. Thus, both potentiation and inhibition of α7 are of therapeutic interest. Cannabidiol (CBD), a non-psychoactive compound with therapeutic potential and broad use, is an α7 modulator. Using patch- clamp recordings, we found that CBD rapidly decreases the frequency of α7 activation episodes while also inducing delayed, prolonged openings, suggesting multiple binding sites or mechanisms. To predict binding sites, we performed coarse-grained molecular dynamics simulations of α7 in resting and desensitized states embedded in a POPC:POPA:CHOL membrane in the presence of CBD. Several potential sites were identified. Representative structures were backmapped to atomistic detail and simulated to analyze stability and interactions. In the desensitized state, two residues from M4 interacted with CBD, while two others from M1 contributed to the resting site. Furthermore, one residue from the Cys-loop was involved in both states. These residues define a putative CBD binding domain located at the extracellular-facing apex of the M1 and M4 helices. To test their functional contribution, residues were mutated to alanine and electrophysiological recordings were performed. Mutants displayed altered responses to CBD: some mutations primarily reduced sensitivity to inhibition by affecting opening frequency, whereas others prolonged activation episodes by modifying channel kinetics. These effects did not segregate strictly by site, as residues from different locations showed overlapping functional roles. Taken together, our results support the existence of a CBD binding domain that allosterically modulates α7. Understanding these mechanisms is crucial for the rational therapeutic use of CBD and for anticipating possible adverse effects.
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. 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
LIII Reunión Anual de la Sociedad Argentina de Biofísica
Buenos Aires
Argentina
Sociedad Argentina de Biofísica
Universidad Nacional de Buenos Aires
description The α7 nicotinic acetylcholine receptor is a homopentameric ligand-gated ion channel widely expressed in the brain and also present in non-neuronal cells. It contributes to cognition, memory, neuroprotection, and the control of inflammation. Reduced α7 activity has been associated with neurological and neurodegenerative disorders, whereas enhanced activity may promote cancer progression. Thus, both potentiation and inhibition of α7 are of therapeutic interest. Cannabidiol (CBD), a non-psychoactive compound with therapeutic potential and broad use, is an α7 modulator. Using patch- clamp recordings, we found that CBD rapidly decreases the frequency of α7 activation episodes while also inducing delayed, prolonged openings, suggesting multiple binding sites or mechanisms. To predict binding sites, we performed coarse-grained molecular dynamics simulations of α7 in resting and desensitized states embedded in a POPC:POPA:CHOL membrane in the presence of CBD. Several potential sites were identified. Representative structures were backmapped to atomistic detail and simulated to analyze stability and interactions. In the desensitized state, two residues from M4 interacted with CBD, while two others from M1 contributed to the resting site. Furthermore, one residue from the Cys-loop was involved in both states. These residues define a putative CBD binding domain located at the extracellular-facing apex of the M1 and M4 helices. To test their functional contribution, residues were mutated to alanine and electrophysiological recordings were performed. Mutants displayed altered responses to CBD: some mutations primarily reduced sensitivity to inhibition by affecting opening frequency, whereas others prolonged activation episodes by modifying channel kinetics. These effects did not segregate strictly by site, as residues from different locations showed overlapping functional roles. Taken together, our results support the existence of a CBD binding domain that allosterically modulates α7. Understanding these mechanisms is crucial for the rational therapeutic use of CBD and for anticipating possible adverse effects.
publishDate 2025
dc.date.none.fl_str_mv 2025
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/11336/289823
Identification of a Cannabidiol Binding Domain Involved in the Allosteric Modulation of the alpha7 Nicotinic Acetylcholine Receptor; LIII Reunión Anual de la Sociedad Argentina de Biofísica; Buenos Aires; Argentina; 2025; 86-86
978-987-48938-3-3
CONICET Digital
CONICET
url http://hdl.handle.net/11336/289823
identifier_str_mv Identification of a Cannabidiol Binding Domain Involved in the Allosteric Modulation of the alpha7 Nicotinic Acetylcholine Receptor; LIII Reunión Anual de la Sociedad Argentina de Biofísica; Buenos Aires; Argentina; 2025; 86-86
978-987-48938-3-3
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-2025/#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
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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