Department of Biochemistry, Duke University Medical Center, Durham, NC 27710.
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710.
Proc Natl Acad Sci U S A. 2022 Mar 22;119(12):e2200140119. doi: 10.1073/pnas.2200140119. Epub 2022 Mar 14.
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.
越来越多的与功能获得（gain-of-function，GOF）相关的 BK 通道病已在癫痫和运动障碍患者中被鉴定出来。然而，其潜在的病理生理学和相应的治疗方法仍然不清楚。在这里，我们利用携带人类 BK-D434G 通道病的基因敲入小鼠模型来研究 BK GOF 在癫痫和运动障碍发病机制中的神经元机制。BK-D434G 小鼠表现出失神性癫痫的临床特征，并表现出严重的运动缺陷和运动障碍样行为。来自 BK-D434G 小鼠的皮质锥体神经元和小脑浦肯野细胞表现出过度兴奋，这可能有助于失神性癫痫发作和阵发性运动障碍的发病机制。BK 通道阻滞剂 paxilline 可有效抑制 BK-D434G 诱导的过度兴奋，并显著减轻小鼠的失神性癫痫发作和运动功能障碍。因此，本研究揭示了 BK GOF 在失神性癫痫和运动障碍中的神经元机制。我们的研究结果还表明，BK 抑制可能是减轻 BK GOF 诱导的神经障碍的一种有前途的治疗策略。
