Elucidating Cannabidiol Binding Sites On The α7 Nicotinic Acetylcholine Receptor

Autores
Chrestia, Juan Facundo; Viscarra, Franco; Bermudez, 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 ACh-gated channel present in the nervous system and in non-neuronal cells. Reduced activity of α7 has been linked to neurological and neurodegenerative disorders, while increased activity could contribute to cancer progression. α7 is a target of cannabidiol (CBD), which is of great interest due to its widespread use, therapeutic properties, and lack of psychoactive effects. By patch clamp recordings, we showed that CBD mediates two distinct actions on α7 function occurring at different time scales. CBD rapidly inhibits the frequency of activation episodes, while after several minutes, it causes an additional delayed effect evidenced by the appearance of prolonged activation episodes. To predict the binding sites of CBD, we performed molecular dynamics simulations of α7 and CBD in coarse-grained representation. α7 resting and desensitized states were embedded in a POPC:POPA:CHOL membrane and simulated in the presence ofCBDmolecules. Several potential binding sites were identified for both receptor states. Representative structures were backmapped to atomistic representation and each one was simulated to gain deeper insight into the stability and interactions. In both states, themost stable binding site was located in the top portion of the extracellular domain. Contact analysis was performed and several residues were selected for mutagenesis studies. Compared to the wild-type receptor, electrophysiological recordings with mutants showed different responses to CBD, ranging from reduced sensitivity for the rapid inhibitory effect to increased sensitivity for the kinetic changes. These results confirm the involvement of the candidate residues in the allosteric mechanism underlying CBD´s effect on α7 and suggest that different residues govern the different 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; Reino Unido. University of Oxford; Reino Unido
Fil: Bermudez, Isabel. Oxford Brookes University; Reino Unido
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
LVI Reunión Anual Asociación Argentina de Farmacología Experimental
Bahía Blanca
Argentina
Asociación Argentina de Farmacología experimental
Universidad Nacional del Sur
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-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/277919
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/277919
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Elucidating Cannabidiol Binding Sites On The α7 Nicotinic Acetylcholine ReceptorChrestia, Juan FacundoViscarra, FrancoBermudez, IsabelBouzat, Cecilia BeatrizALPHA 7 NICOTINIC RECEPTORCANNABIDIOLMOLECULAR DYNAMIC SIMULATIONPATCH-CLAMPhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The α7 nicotinic receptor is an ACh-gated channel present in the nervous system and in non-neuronal cells. Reduced activity of α7 has been linked to neurological and neurodegenerative disorders, while increased activity could contribute to cancer progression. α7 is a target of cannabidiol (CBD), which is of great interest due to its widespread use, therapeutic properties, and lack of psychoactive effects. By patch clamp recordings, we showed that CBD mediates two distinct actions on α7 function occurring at different time scales. CBD rapidly inhibits the frequency of activation episodes, while after several minutes, it causes an additional delayed effect evidenced by the appearance of prolonged activation episodes. To predict the binding sites of CBD, we performed molecular dynamics simulations of α7 and CBD in coarse-grained representation. α7 resting and desensitized states were embedded in a POPC:POPA:CHOL membrane and simulated in the presence ofCBDmolecules. Several potential binding sites were identified for both receptor states. Representative structures were backmapped to atomistic representation and each one was simulated to gain deeper insight into the stability and interactions. In both states, themost stable binding site was located in the top portion of the extracellular domain. Contact analysis was performed and several residues were selected for mutagenesis studies. Compared to the wild-type receptor, electrophysiological recordings with mutants showed different responses to CBD, ranging from reduced sensitivity for the rapid inhibitory effect to increased sensitivity for the kinetic changes. These results confirm the involvement of the candidate residues in the allosteric mechanism underlying CBD´s effect on α7 and suggest that different residues govern the different 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; Reino Unido. University of Oxford; Reino UnidoFil: Bermudez, Isabel. Oxford Brookes University; Reino UnidoFil: 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; ArgentinaLVI Reunión Anual Asociación Argentina de Farmacología ExperimentalBahía BlancaArgentinaAsociación Argentina de Farmacología experimentalUniversidad Nacional del SurAsociación Argentina de Farmacología Experimental2024info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/277919Elucidating Cannabidiol Binding Sites On The α7 Nicotinic Acetylcholine Receptor; LVI Reunión Anual Asociación Argentina de Farmacología Experimental; Bahía Blanca; Argentina; 2024; 45-45CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://aafeargentina.org/congresos-aafe/Nacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-12-23T14:34:03Zoai:ri.conicet.gov.ar:11336/277919instacron: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:34982025-12-23 14:34:04.039CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Elucidating Cannabidiol Binding Sites On The α7 Nicotinic Acetylcholine Receptor
title Elucidating Cannabidiol Binding Sites On The α7 Nicotinic Acetylcholine Receptor
spellingShingle Elucidating Cannabidiol Binding Sites On The α7 Nicotinic Acetylcholine Receptor
Chrestia, Juan Facundo
ALPHA 7 NICOTINIC RECEPTOR
CANNABIDIOL
MOLECULAR DYNAMIC SIMULATION
PATCH-CLAMP
title_short Elucidating Cannabidiol Binding Sites On The α7 Nicotinic Acetylcholine Receptor
title_full Elucidating Cannabidiol Binding Sites On The α7 Nicotinic Acetylcholine Receptor
title_fullStr Elucidating Cannabidiol Binding Sites On The α7 Nicotinic Acetylcholine Receptor
title_full_unstemmed Elucidating Cannabidiol Binding Sites On The α7 Nicotinic Acetylcholine Receptor
title_sort Elucidating Cannabidiol Binding Sites On The α7 Nicotinic Acetylcholine Receptor
dc.creator.none.fl_str_mv Chrestia, Juan Facundo
Viscarra, Franco
Bermudez, Isabel
Bouzat, Cecilia Beatriz
author Chrestia, Juan Facundo
author_facet Chrestia, Juan Facundo
Viscarra, Franco
Bermudez, Isabel
Bouzat, Cecilia Beatriz
author_role author
author2 Viscarra, Franco
Bermudez, Isabel
Bouzat, Cecilia Beatriz
author2_role author
author
author
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 receptor is an ACh-gated channel present in the nervous system and in non-neuronal cells. Reduced activity of α7 has been linked to neurological and neurodegenerative disorders, while increased activity could contribute to cancer progression. α7 is a target of cannabidiol (CBD), which is of great interest due to its widespread use, therapeutic properties, and lack of psychoactive effects. By patch clamp recordings, we showed that CBD mediates two distinct actions on α7 function occurring at different time scales. CBD rapidly inhibits the frequency of activation episodes, while after several minutes, it causes an additional delayed effect evidenced by the appearance of prolonged activation episodes. To predict the binding sites of CBD, we performed molecular dynamics simulations of α7 and CBD in coarse-grained representation. α7 resting and desensitized states were embedded in a POPC:POPA:CHOL membrane and simulated in the presence ofCBDmolecules. Several potential binding sites were identified for both receptor states. Representative structures were backmapped to atomistic representation and each one was simulated to gain deeper insight into the stability and interactions. In both states, themost stable binding site was located in the top portion of the extracellular domain. Contact analysis was performed and several residues were selected for mutagenesis studies. Compared to the wild-type receptor, electrophysiological recordings with mutants showed different responses to CBD, ranging from reduced sensitivity for the rapid inhibitory effect to increased sensitivity for the kinetic changes. These results confirm the involvement of the candidate residues in the allosteric mechanism underlying CBD´s effect on α7 and suggest that different residues govern the different 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; Reino Unido. University of Oxford; Reino Unido
Fil: Bermudez, Isabel. Oxford Brookes University; Reino Unido
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
LVI Reunión Anual Asociación Argentina de Farmacología Experimental
Bahía Blanca
Argentina
Asociación Argentina de Farmacología experimental
Universidad Nacional del Sur
description The α7 nicotinic receptor is an ACh-gated channel present in the nervous system and in non-neuronal cells. Reduced activity of α7 has been linked to neurological and neurodegenerative disorders, while increased activity could contribute to cancer progression. α7 is a target of cannabidiol (CBD), which is of great interest due to its widespread use, therapeutic properties, and lack of psychoactive effects. By patch clamp recordings, we showed that CBD mediates two distinct actions on α7 function occurring at different time scales. CBD rapidly inhibits the frequency of activation episodes, while after several minutes, it causes an additional delayed effect evidenced by the appearance of prolonged activation episodes. To predict the binding sites of CBD, we performed molecular dynamics simulations of α7 and CBD in coarse-grained representation. α7 resting and desensitized states were embedded in a POPC:POPA:CHOL membrane and simulated in the presence ofCBDmolecules. Several potential binding sites were identified for both receptor states. Representative structures were backmapped to atomistic representation and each one was simulated to gain deeper insight into the stability and interactions. In both states, themost stable binding site was located in the top portion of the extracellular domain. Contact analysis was performed and several residues were selected for mutagenesis studies. Compared to the wild-type receptor, electrophysiological recordings with mutants showed different responses to CBD, ranging from reduced sensitivity for the rapid inhibitory effect to increased sensitivity for the kinetic changes. These results confirm the involvement of the candidate residues in the allosteric mechanism underlying CBD´s effect on α7 and suggest that different residues govern the different effects.
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/11336/277919
Elucidating Cannabidiol Binding Sites On The α7 Nicotinic Acetylcholine Receptor; LVI Reunión Anual Asociación Argentina de Farmacología Experimental; Bahía Blanca; Argentina; 2024; 45-45
CONICET Digital
CONICET
url http://hdl.handle.net/11336/277919
identifier_str_mv Elucidating Cannabidiol Binding Sites On The α7 Nicotinic Acetylcholine Receptor; LVI Reunión Anual Asociación Argentina de Farmacología Experimental; Bahía Blanca; Argentina; 2024; 45-45
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://aafeargentina.org/congresos-aafe/
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
application/pdf
dc.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv Asociación Argentina de Farmacología Experimental
publisher.none.fl_str_mv Asociación Argentina de Farmacología Experimental
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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