Mutant Analysis of a Novel High Conductance K+ Channel

描述（由申请人提供）：一种比较基因组学方法，始于对秀丽隐杆线虫中不寻常的slow -2基因的分析，导致了长期追求的哺乳动物Na+激活钾通道（KNa）的分子鉴定。KNa通道已经在心肌细胞和神经元中被发现，在那里它们可能作为对抗缺血的重要保护机制（Dryer, 1994）。我们的研究表明秀丽隐杆线虫的基因slow -2也具有抗缺氧能力（Yuan et al .，提交）。我们的研究进一步表明，哺乳动物的KNa通道是由rSlack基因（Joiner, et al, 1998） （rslo2）编码的，该基因是线虫slow -2基因的哺乳动物同源物。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通道在不同类别的已识别神经元中的作用（在秀丽隐杆线虫中），克隆和功能表征人类（和小鼠）基因组中存在的两个不同的哺乳动物SLO-2基因，并确定哺乳动物SLO-2通道中负责感知Na +和CI-显著特性的结构区域，来进一步研究这些发现。除了扩展我们对离子通道激活因素的理论理解外，这一信息可能对临床应用很重要。

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.