Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia.
Ping DongYang ZhangArsen S HunanyanMohamad A MikatiJianmin CuiHuanghe YangPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- mouse model
- traumatic brain injury
- endothelial cells
- high glucose
- high fat diet induced
- atrial fibrillation
- metabolic syndrome
- spinal cord
- small molecule
- diabetic rats
- oxidative stress
- radiation therapy
- signaling pathway
- insulin resistance
- blood brain barrier
- subarachnoid hemorrhage
- angiotensin ii
- angiotensin converting enzyme
- pluripotent stem cells
- catheter ablation