Glial regulation of extracellular potassium (K+) helps to maintain appropriate levels of neuronal excitability. While channels and transporters mediating K+ and water transport are known, little is understood about upstream regulatory mechanisms controlling the glial capacity to buffer K+ and osmotically obliged water. Here we identify salt-inducible kinase 3 (SIK3) as the central node in a signal transduction pathway controlling glial K+ and water homeostasis in Drosophila. Loss of SIK3 leads to dramatic extracellular fluid accumulation in nerves, neuronal hyperexcitability, and seizures. SIK3-dependent phenotypes are exacerbated by K+ stress. SIK3 promotes the cytosolic localization of HDAC4, thereby relieving inhibition of Mef2-dependent transcription of K+ and water transport molecules. This transcriptional program controls the glial capacity to regulate K+ and water homeostasis and modulate neuronal excitability. We identify HDAC4 as a candidate therapeutic target in this pathway, whose inhibition can enhance the K+ buffering capacity of glia, which may be useful in diseases of dysregulated K+ homeostasis and hyperexcitability.

中文翻译：

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SIK3 通过调节神经胶质细胞缓冲 K+ 和水的能力来抑制神经元过度兴奋

神经胶质细胞对细胞外钾 (K+) 的调节有助于维持神经元兴奋性的适当水平。虽然介导 K+ 和水运输的通道和转运蛋白是已知的，但对控制神经胶质缓冲 K+ 和渗透水的能力的上游调节机制了解甚少。在这里，我们将盐诱导激酶 3 (SIK3) 确定为控制果蝇神经胶质 K+ 和水稳态的信号转导途径的中心节点。SIK3 的缺失会导致神经细胞外液大量积聚、神经元过度兴奋和癫痫发作。K+ 应激会加剧 SIK3 依赖性表型。SIK3 促进 HDAC4 的胞质定位，从而减轻对 Mef2 依赖性 K+ 和水转运分子转录的抑制。该转录程序控制神经胶质细胞调节 K+ 和水稳态以及调节神经元兴奋性的能力。我们将 HDAC4 确定为该通路中的候选治疗靶点，其抑制作用可以增强神经胶质细胞的 K+ 缓冲能力，这可能有助于治疗 K+ 稳态失调和过度兴奋的疾病。