Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523.
Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523
J Neurosci. 2021 Oct 27;41(43):9047-9063. doi: 10.1523/JNEUROSCI.0290-21.2021. Epub 2021 Sep 20.
Na sensitivity is a unique feature of Na-activated K (K) channels, making them naturally suited to counter a sudden influx in Na ions. As such, it has long been suggested that K channels may serve a protective function against excessive excitation associated with neuronal injury and disease. This hypothesis, however, has remained largely untested. Here, we examine K channels encoded by the () gene in males and females. We show that dSlo2/K channels are selectively expressed in cholinergic neurons in the adult brain, as well as in glutamatergic motor neurons, where dampening excitation may function to inhibit global hyperactivity and seizure-like behavior. Indeed, we show that effects of feeding a cholinergic agonist are exacerbated by the loss of dSlo2/K channels. Similar to mammalian Slo2/K channels, we show that dSlo2/K channels encode a TTX-sensitive K conductance, indicating that dSlo2/K channels can be activated by Na carried by voltage-dependent Na channels. We then tested the role of dSlo2/K channels in established genetic seizure models in which the voltage-dependent persistent Na current (I) is elevated. We show that the absence of dSlo2/K channels increased susceptibility to mechanically induced seizure-like behavior. Similar results were observed in WT flies treated with veratridine, an enhancer of I Finally, we show that loss of dSlo2/K channels in both genetic and pharmacologically primed seizure models resulted in the appearance of spontaneous seizures. Together, our results support a model in which dSlo2/K channels, activated by neuronal overexcitation, contribute to a protective threshold to suppress the induction of seizure-like activity. Slo2/K channels are unique in that they constitute a repolarizing K pore that is activated by the depolarizing Na ion, making them naturally suited to function as a protective "brake" against overexcitation and Na overload. Here, we test this hypothesis by examining how a null mutation of the ()/ gene affects seizure-like behavior in genetic and pharmacological models of epilepsy. We show that indeed the loss of dSlo2/K channels results in increased incidence and severity of induced seizure behavior, as well as the appearance of spontaneous seizure activity. Our results advance our understanding of neuronal excitability and protective mechanisms that preserve normal physiology and the suppression of seizure susceptibility.
钠敏是钠激活钾 (K) 通道的独特特征，使它们自然适合对抗钠离子的突然涌入。因此，长期以来，人们一直认为 K 通道可能在对抗与神经元损伤和疾病相关的过度兴奋方面发挥保护作用。然而，这一假说在很大程度上仍未得到验证。在这里，我们检查了 () 基因在雄性和雌性中编码的 K 通道。我们表明，dSlo2/K 通道选择性地在成年大脑中的胆碱能神经元以及谷氨酸能运动神经元中表达，在这些神经元中，抑制兴奋可能起到抑制整体过度活跃和类似癫痫发作的行为的作用。事实上，我们表明，用胆碱能激动剂喂养会加剧 dSlo2/K 通道缺失的影响。与哺乳动物 Slo2/K 通道类似，我们表明 dSlo2/K 通道编码一种 TTX 敏感的 K 电导，表明 dSlo2/K 通道可以被电压依赖性钠通道携带的钠激活。然后，我们在电压依赖性持久钠电流 (I) 升高的既定遗传癫痫模型中测试了 dSlo2/K 通道的作用。我们表明，dSlo2/K 通道缺失会增加对机械诱导的类似癫痫发作行为的易感性。在用维拉帕米处理的 WT 果蝇中观察到类似的结果，维拉帕米是 I 的增强剂。最后，我们表明，在遗传和药理学引发的癫痫模型中，dSlo2/K 通道的缺失导致自发癫痫的出现。总的来说，我们的结果支持这样一种模型，即 dSlo2/K 通道通过神经元过度兴奋激活，有助于建立一个保护性的“刹车”，以抑制类似癫痫发作活动的诱导。Slo2/K 通道是独特的，因为它们构成了一种由去极化钠激活的再极化 K 孔，使它们自然适合作为对抗过度兴奋和钠过载的保护性“刹车”。在这里，我们通过检查 ()/ 基因的 null 突变如何影响癫痫的遗传和药理学模型中的类似癫痫发作行为来检验这一假设。我们表明，dSlo2/K 通道的缺失确实会导致诱导的癫痫行为的发生率和严重程度增加，以及自发癫痫活动的出现。我们的结果增进了我们对神经元兴奋性和保护机制的理解，这些机制维持了正常的生理学和抑制癫痫易感性。
