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
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.
