Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant

Xiaoqin Zhan; Chris Drummond-Main; Dylan Greening; Jinjing Yao; S.W.R. Chen; J.P. Appendino; P. Y. Billie Au; Ray W. Turner

iScience (Oct 2022)

Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant

Xiaoqin Zhan,
Chris Drummond-Main,
Dylan Greening,
Jinjing Yao,
S.W.R. Chen,
J.P. Appendino,
P. Y. Billie Au,
Ray W. Turner

Affiliations

Xiaoqin Zhan: Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada
Chris Drummond-Main: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada
Dylan Greening: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada
Jinjing Yao: Libin Cardiovascular Research Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada
S.W.R. Chen: Libin Cardiovascular Research Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada
J.P. Appendino: Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Pediatric Department, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
P. Y. Billie Au: Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Department of Medical Genetics, University of Calgary, Calgary, Alberta T2N 4N1, Canada
Ray W. Turner: Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Corresponding author

Journal volume & issue: Vol. 25, no. 10
p. 105092

Abstract

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Summary: Epilepsy and neurodevelopmental disorders can arise from pathogenic variants of KCNQ (Kv7) channels. A patient with developmental and epileptic encephalopathy exhibited an in-frame deletion of histidine 260 on Kv7.2. Coexpression of Kv7.2 mutant (mut) subunits with Kv7.3 invoked a decrease in current density, a depolarizing shift in voltage for activation, and a decrease in membrane conductance. Biotinylation revealed an increased level of surface Kv7.2mut compared to Kv7.3 with no change in total membrane protein expression. Super-resolution and FRET imaging confirmed heteromeric channel formation and a higher expression density of Kv7.2mut. Cannabidiol (1 μM) offset the effects of Kv7.2mut by inducing a hyperpolarizing shift in voltage for activation independent of CB1 or CB2 receptors. These data reveal that the ability for cannabidiol to reduce the effects of a pathogenic Kv7.2 variant supports its use as a potential therapeutic to reduce seizure activity.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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