Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia.

Journal Article (Journal Article)

A growing number of gain-of-function (GOF) BK channelopathies have been identified in patients with epilepsy and movement disorders. Nevertheless, the underlying pathophysiology and corresponding therapeutics remain obscure. Here, we utilized a knock-in mouse model carrying human BK-D434G channelopathy to investigate the neuronal mechanism of BK GOF in the pathogenesis of epilepsy and dyskinesia. The BK-D434G mice manifest the clinical features of absence epilepsy and exhibit severe motor deficits and dyskinesia-like behaviors. The cortical pyramidal neurons and cerebellar Purkinje cells from the BK-D434G mice show hyperexcitability, which likely contributes to the pathogenesis of absence seizures and paroxysmal dyskinesia. A BK channel blocker, paxilline, potently suppresses BK-D434G–induced hyperexcitability and effectively mitigates absence seizures and locomotor deficits in mice. Our study thus uncovered a neuronal mechanism of BK GOF in absence epilepsy and dyskinesia. Our findings also suggest that BK inhibition is a promising therapeutic strategy for mitigating BK GOF-induced neurological disorders.

Full Text

Duke Authors

Cited Authors

  • Dong, P; Zhang, Y; Hunanyan, AS; Mikati, MA; Cui, J; Yang, H

Published Date

  • March 22, 2022

Published In

Volume / Issue

  • 119 / 12

Start / End Page

  • e2200140119 -

PubMed ID

  • 35286197

Pubmed Central ID

  • PMC8944272

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.2200140119


  • eng

Conference Location

  • United States