Cannabidiol interactions with voltage-gated sodium channels.
cannabidiol
crystal structure
drug interations
electrophysiology
molecular biophysics
none
structural biology
structure-function relationships
voltage -gated sodium channel
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
22 10 2020
22 10 2020
Historique:
received:
05
05
2020
accepted:
15
10
2020
pubmed:
23
10
2020
medline:
4
3
2021
entrez:
22
10
2020
Statut:
epublish
Résumé
Voltage-gated sodium channels are targets for a range of pharmaceutical drugs developed for the treatment of neurological diseases. Cannabidiol (CBD), the non-psychoactive compound isolated from cannabis plants, was recently approved for treatment of two types of epilepsy associated with sodium channel mutations. This study used high-resolution X-ray crystallography to demonstrate the detailed nature of the interactions between CBD and the NavMs voltage-gated sodium channel, and electrophysiology to show the functional effects of binding CBD to these channels. CBD binds at a novel site at the interface of the fenestrations and the central hydrophobic cavity of the channel. Binding at this site blocks the transmembrane-spanning sodium ion translocation pathway, providing a molecular mechanism for channel inhibition. Modelling studies suggest why the closely-related psychoactive compound tetrahydrocannabinol may not have the same effects on these channels. Finally, comparisons are made with the TRPV2 channel, also recently proposed as a target site for CBD. In summary, this study provides novel insight into a possible mechanism for CBD interactions with sodium channels.
Identifiants
pubmed: 33089780
doi: 10.7554/eLife.58593
pii: 58593
pmc: PMC7641581
doi:
pii:
Substances chimiques
Voltage-Gated Sodium Channels
0
Cannabidiol
19GBJ60SN5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Natural Science and Engineering Research Council of Canada
ID : RGPIN03920
Pays : International
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/C500628/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/L006790
Pays : United Kingdom
Organisme : Rosetrees Trust
ID : M848
Pays : International
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/H023852/1
Pays : United Kingdom
Organisme : Rare Disease Foundation
ID : 00000
Pays : International
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/F010346/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/H01070X/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BBS/B/02959
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/G023476/1
Pays : United Kingdom
Organisme : Natural Science and Engineering Research Council of Canada
ID : CGS-D:535333-2019
Pays : International
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/R001294
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/D008581/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/F009143/1
Pays : United Kingdom
Informations de copyright
© 2020, Sait et al.
Déclaration de conflit d'intérêts
LS, AS, MG, DH, PR, BW No competing interests declared
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