Glial KCNQ channels.

项目摘要/摘要 KCNQ通道是一个保守的电压门控钾通道家族的成员。KCNQ2至 KCNQ5亚单位在神经系统中表达，在那里它们调节神经元的兴奋性。癫痫， 自闭症和其他神经疾病与KCNQ通道基因突变有关 在神经系统中表达。尽管证据支持KCNQ通道的表达，但在 在神经元和神经胶质细胞中，这些通道在神经胶质细胞中的作用尚不清楚。在本研究中，我们使用C。 研究神经胶质细胞KCNQ通道的生理功能及其对神经胶质细胞的影响 KCNQ致病突变。通过RNA测序，我们发现了两性胶质细胞，一对胶质细胞 将感觉神经元包裹在两栖感觉器官中，表达KCNQ蠕虫同源物KQT- 2.初步的行为学和钙成像实验表明，KQT-2神经胶质细胞释放的GABA减少 击倒和神经胶质击倒蠕虫。重要的是，人KCNQ2和KCNQ3在两性胶质细胞中的表达 基因拯救KQT-2基因敲除表型，支持跨物种的功能保守。因此，我们的 初步结果提示，胶质细胞可能需要胶质细胞KCNQ通道来抑制神经元的活动。 GABA释放。在本应用程序中，我们将通过以下3个具体目标来检验这一假设：1) 确定在KQT-2基因敲除中神经胶质细胞和神经元的功能发生了多大程度的改变；2)确定 神经胶质细胞中KCNQ通道的生理特性；以及3)建立神经胶质细胞KCNQ的后果 神经胶质和神经元结构和功能的致病突变。我们的发现表明了一种范式的转变： 神经元的输出不仅受神经元KCNQ通道的调节，也受神经胶质KCNQ的调节。我们的工作将 阐明了这一调节的潜在机制，并将确定致病因子的贡献 胶质细胞KCNQ突变对表型表达的影响。

Project Summary/Abstract KCNQ channels are members of a conserved family of voltage-gated potassium channels. KCNQ2 through KCNQ5 subunits are expressed in the nervous system, where they regulate neuronal excitability. Epilepsy, autism, and other neurological conditions have been associated with mutations in the KCNQ channel genes expressed in the nervous system. Although evidence supports the expression of KCNQ channels both in neurons and in glia, the role of these channels in glial cells is still unknown. In this study, we use C. elegans to investigate the physiological function of KCNQ channels in glia and the consequences of glial KCNQ pathogenic mutations. Using RNA sequencing we have found that the amphid glia, a pair of glial cells that encapsulate sensory neurons in the amphid sensory organ, express KCNQ worm homolog kqt- 2. Preliminary behavioral and Ca2+ imaging experiments suggest reduced GABA release from glia of kqt-2 knockout and glial knock down worms. Importantly, expression in amphid glia of human KCNQ2 and KCNQ3 genes rescue the kqt-2 knockout phenotype, supporting conservation of function across species. Thus, our preliminary results suggest that glial KCNQ channels may be needed in glia to dampen neuronal activity via GABA release. In this application we will test this hypothesis through the following 3 specific aims: 1) To establish to what extent the function of glia and neurons is altered in kqt-2 knockout; 2) To determine the physiological properties of KCNQ channels in glia; and 3) To establish the consequences of glial KCNQ pathogenic mutations on glial and neuronal structure and function. Our findings suggest a paradigm shift: neuronal output is regulated not only by neuronal KCNQ channels but also by glial KCNQs. Our work will shed light on the underlying mechanism of this regulation and will determine the contribution of pathogenic glial KCNQ mutation to the expression of the phenotype.