Mutant Analysis of a Novel High Conductance K+ Channel

描述（由申请人提供）：一种比较基因组方法，从分析C. elegans的研究已经导致了长期寻求的哺乳动物Na+激活钾通道（KNa）的分子鉴定。KNa通道在心肌细胞和神经元中已被鉴定，它们可作为抗缺血的重要保护机制（Dryer，1994）。我们的研究表明，C.秀丽线虫基因，β-2，也赋予对缺氧的抗性（Yuan等，提交）。我们的研究进一步表明哺乳动物KNa通道由rSlack基因（Joiner等，1998）（rslo 2）编码，rSlack基因是C. elegans nucleus-2基因。我们发现rSLO-2通道具有天然KNa通道的所有特性。我们现在计划通过研究SLO-2通道在不同类型的已鉴定神经元中的作用来跟踪这些发现（在C。elegans），克隆和功能性表征存在于人（和小鼠）基因组中的两个不同的哺乳动物SLO-2基因，并定义哺乳动物SLO-2通道中负责感测Na +和Cl-的显著特性的结构区域。除了扩展我们对离子通道激活因素的理论理解外，这些信息对临床应用可能很重要。 调节KNa通道的药物，特别是通道开放剂，可能在预防心脏缺血和中风期间的细胞损伤中起有用的作用，并且可能在移植手术中使用的器官的预处理中起保护剂的作用。

DESCRIPTION (provided by applicant): A comparative genomic approach, which began with the analysis of the unusual slo-2 gene in C. elegans has led to the molecular identification of the long sought-after mammalian Na+-activated potassium channel (KNa). KNa channels have been identified in cardiomyocytes and neurons where they may serve as an important protective mechanism against ischemia (Dryer, 1994). Our studies showed that the C. elegans gene, slo-2, also confers resistance to hypoxia (Yuan et al, submitted). Our studies further showed that mammalian KNa channels are encoded by the rSlack gene (Joiner, et al, 1998) (rslo2), a mammalian orthologue of the C. elegans slo-2 gene. We showed that rSLO-2 channels have all the properties of native KNa channels. We now plan to follow up on these findings by investigating the role of SLO-2 channels in different classes of identified neurons (in C. elegans), cloning and functionally characterizing two distinct mammalian slo-2 genes present in human (and mouse) genomes, and defining the structural regions in mammalian SLO-2 channels which are responsible for the salient property of sensing Na + and CI-. In addition to extending our theoretical understanding of the factors involved in ion channel activation, this information may be important for clinical applications. Pharmacological agents which modulate the KNa channel, especially channel openers, might serve a useful role in preventing cell damage during cardiac ischemia and stroke, and may serve as a protective agent in the pretreatment of organs used in transplant procedures.