NIL-16: A Link Between Ion Channels and Cytokines

描述(由申请人提供)： 这个项目的长期目标是阐明相互之间和 神经元内信号转导有助于神经元的发育和功能。 神经元间通讯发生在突触；突触形成的中断 在发育中和成年人类中的功能导致无数的神经和 精神障碍，包括精神分裂症、躁郁症和学习障碍 残疾人士。 在这里提出的研究的目的是要调查的生物学作用 神经系统中的PDZ结构域蛋白NIL-16。NIL-16是唯一的 双官能团，既可以作为特定的离子通道结合分子，也可以作为 细胞因子的神经元特异性前体，白介素16。 16被克隆，IL-16仅在免疫系统中被鉴定。这个 对NIL-16的鉴定显示，在免疫系统中 和神经系统。IL-16在神经元中诱导信号级联，导致 转录因子Fos的上调。因此，NIL-16代表 细胞因子信号转导与离子通道功能之间的第一个分子联系。 值得注意的是，初步研究表明，nIL-16可以结合CD4，一种功能性的 免疫系统中的IL-16受体。这些发现表明，NIL-16可能 既是IL-16的前体，又是其分子锚 受体。此外，由于NIL-16还结合离子通道，IL-16信号转导 可能最终调节离子通道的功能。这些研究有三个 具体目标： 1)检验NIL-16充当脚手架或贩运的假设 利用电生理影响离子通道功能的蛋白质 记录，免疫沉淀，免疫荧光共聚焦显微镜，和 内吞试验； 2)验证存在特定的IL-16信号通路的假设 突变小鼠的神经元研究，化学交联性研究，激酶和 磷酸化分析，亚细胞定位研究，以及 电生理记录；以及 3)检验nIL-16影响长时程增强(LTP)的假设 通过比较野生型脑组织的电生理记录 和nIL-16缺陷小鼠。

DESCRIPTION (provided by applicant): The long-term goal of this project is to elucidate how inter- and intra-neuronal signaling contributes to neuronal development and function. Interneuronal communication occurs at synapses; disruption of synapse formation and function in developing and adult humans causes myriad neurological and psychiatric disorders, including schizophrenia, bipolar disease, and learning disabilities. The goal of the studies proposed here is to investigate the biological role of the PDZ domain protein NIL-16 in the nervous system. NIL-16 is uniquely bifunctional, serving both as a specific ion channel binding molecule and as the neuron-specific precursor of the cytokine, interleukin (IL)- 16. Until NIL- 16 was cloned, IL16 had been characterized only in the immune system. The identification of NIL-16 revealed an unsuspected parallel between the immune and nervous systems. IL-16 induces a signaling cascade in neurons that leads to upregulation of the transcription factor Fos. Therefore, NIL- 16 represents the first molecular link between cytokine signaling and ion channel function. Remarkably, preliminary studies revealed that NIL-16 can bind CD4, a functional IL- 16 receptor in the immune system. These findings suggest that NIL- 16 may function as both the precursor of IL- 16 and the molecular anchor for its receptor. Moreover, because NIL- 16 also binds ion channels, IL- 16 signaling may ultimately modulate the function of ion channels. These studies have three specific aims: 1) To test the hypothesis that NIL-16 serves as a scaffolding or trafficking protein that influences ion channel function by using electrophysiological recordings, immunoprecipitation, immunofluorescence confocal microscopy, and endocytosis assays; 2) To test the hypothesis that there is a specific IL-16 signaling pathway in neurons by studies in mutant mice, chemical cross-linking studies, kinase and phosphorylation assays, subcellular localization studies, and electrophysiological recordings; and 3) To test the hypothesis that NIL-16 influences long-term potentiation (LTP) by comparative electrophysiological recordings from brain tissue of wild-type and NIL-16-deficient mice.