Mutant Analysis of a Novel High Conductance K+ Channel

新型高电导 K 通道的突变分析

• 批准号: 6681127
• 负责人: LAWRENCE B SALKOFF
• 金额: $ 30.98万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6681127
• 关键词: Caenorhabditis elegans; Xenopus oocyte; cooperative study; electrophysiology; gene expression; hypoxia; immunocytochemistry; laboratory rat; neurons; polymerase chain reaction; potassium channel; site directed mutagenesis; tissue /cell culture; voltage /patch clamp; voltage gated channel

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.

描述（由申请人提供）：一种比较基因组方法，始于对秀丽隐杆线虫中不寻常的 slo-2 基因的分析，导致了长期以来备受追捧的哺乳动物 Na+ 激活钾通道 (KNa) 的分子鉴定。 KNa 通道已在心肌细胞和神经元中被发现，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，线虫基因 slo-2 也具有对缺氧的抵抗力（Yuan 等人提交）。我们的研究进一步表明，哺乳动物 KNa 通道是由 rSlack 基因（Joiner 等，1998）（rslo2）编码的，rSlack 基因是秀丽隐杆线虫 slo-2 基因的哺乳动物直系同源物。我们证明 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（秀丽隐杆线虫）中的作用来跟进这些发现，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，并定义了哺乳动物 SLO-2 通道中负责感知 Na + 和 CI- 的显着特性的结构区域。除了扩展我们对离子通道激活相关因素的理论理解外，这些信息对于临床应用可能很重要。 调节 KNa 通道的药物，尤其是通道开放剂，可能在预防心脏缺血和中风期间的细胞损伤方面发挥有用的作用，并且可以在移植手术中使用的器官的预处理中充当保护剂。