Roles and mechanisms of Slo and Slack Channels in Brain

Slo 和 Slack 通道在大脑中的作用和机制

• 批准号: 6792753
• 负责人: LEONARD K KACZMAREK
• 金额: $ 151.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-04 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6792753
• 关键词: neurobiology; potassium channel; protein structure function

DESCRIPTION (provided by applicant): A class of calcium-activated potassium channels termed BK(Ca) channels are enriched at presynaptic neurotransmitter release sites within the brain, and are believed to control both the amount and timing of neurotransmitter release. BK(Ca) channels are encoded by the Slo gene. Recent evidence suggests that a related gene, Slack, also contributes to BK(Ca)-like channels in neurons, and that some BK(Ca) channels may be comprised of heteromultimers of Slo and Slack channels subunits. The experiments in this proposal will characterize the molecular, biophysical and structural properties of BK(Ca) channels in both the somata and presynaptic terminals of native neurons, and in transfected cells. The role of the Slo and Slack channel subunits in normal synaptic transmission, and the mechanisms of their response to hypoxia, will be determined by patch clamp measurements coupled with genetic knockout approaches. The structure and function of the large carboxy-terminal regulatory region of the Slo channel subunit with its calcium-binding sites, and its interaction with other proteins, including the Slack subunit, will be determined by biophysical and biochemical measurements and by X-ray crystallographic methods. Finally the structure of intact BK(Ca) channels will be determined by cryo-electronmicroscopy. Knowledge of the molecular properties and regulation of BK(Ca) channels in normal and hypoxic neurons, together with structural determinations of their interactions with both drugs and natural ligands, will be key in the development of more effective treatments for disorders such as epilepsy and stroke.

描述（由申请人提供）：一类钙激活 称为BK（CA）通道的钾通道在突触前富集 神经递质释放位点在大脑中，被认为可以控制 神经递质释放的数量和时机。 BK（CA）通道为 由SLO基因编码。最近的证据表明，相关基因，松弛， 还有助于神经元中的BK（CA）样通道，并且一些BK（CA） 通道可以由SLO和Slack通道的异栽培组成 亚基。该提案中的实验将表征分子， BK（CA）通道的生物物理和结构特性，somata和 天然神经元和转染细胞中的突触前末端。的作用 正常突触传播中的SLO和松弛通道亚基，以及 其对缺氧的反应机制将通过斑块夹确定 测量与遗传基因敲除方法相结合。结构和 SLO通道的大型羧基末端调节区的功能 及其钙结合位点的亚基及其与其他的相互作用 包括松弛亚基在内的蛋白质将由生物物理和 生化测量和X射线晶体学方法。最后 完整BK（CA）通道的结构将由 冷冻电子显微镜。了解分子特性和调节 正常和低氧神经元中的BK（CA）通道的结构 确定它们与药物和天然配体的相互作用，将 是开发更有效治疗疾病的关键 癫痫和中风。