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

doi:10.1016/j.isci.2022.105092

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

iScience. 2022 Sep 6;25(10):105092. doi: 10.1016/j.isci.2022.105092. eCollection 2022 Oct 21.

Authors

Xiaoqin Zhan^{1

2}, Chris Drummond-Main², Dylan Greening², Jinjing Yao^{3

2}, S W R Chen^{3

2}, J P Appendino^{1

4}, P Y Billie Au^{1

5}, Ray W Turner^{1

2}

Affiliations

¹ Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
² Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
³ Libin Cardiovascular Research Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
⁴ Pediatric Department, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
⁵ Department of Medical Genetics, University of Calgary, Calgary, Alberta T2N 4N1, Canada.

Abstract

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.

Keywords: Biological sciences; Health sciences; Neuroscience.