MaxiK channel biology

大电导，Ca 2+激活的K+通道（MaxiK，BK）是过多细胞的关键调节因子， 功能包括血管张力、神经元功能和免疫。因此，知道它们的自然成熟 从合成到与蛋白质建立相互作用，引导它们到达功能位点的步骤 是理解其功能基础的关键。因此，本研究的长期目标是确定 MaxiK通道转录的调节机制，共（后）翻译修饰和交通， 在正确的时间和地点确定其可用性和功能。我们已经了解了 MaxiK通道在不同系统中的组成，它们通过沉默在动物生理学中的作用 亚基基因，并已开始掌握信息的机制，他们的细胞交通和他们的 潜在网络我们现在将测试一般假设，即MaxiK的成孔亚基（Slo）基因 和蛋白质具有内在序列，这些序列控制它们的表达、载体运输和蛋白质-脂质相互作用 根据生理需要将它们定位在战略细胞隔室中。我们的初步数据 表明：i. mSlo启动子区对雌激素（E2）有应答，并含有潜在的雌激素应答 可以通过E2控制通道表达的序列; ii.基底外侧MaxiK靶向可能由Slo 剪接变体插入物;和iii.Slo可以被豆蔻酰化。我们将采用多学科方法，特别是， 用量子点和高分辨率显示单分子运动的抗生物素蛋白-Slo结构 共聚焦显微镜具体目的是：1）定位转录起始位点和功能性E2-调控位点， Slo启动子序列，并定义E2介导的Slo调控的基因组机制 2）研究Slo剪接变体在确定差异运输和靶向中的作用; 3）研究MaxiK豆蔻酰化的机制、位点及其功能后果。这些 这些研究将为MaxiK通道基因和蛋白的调控机制提供新的信息 表达和靶向，并确定新的治疗途径，以减轻心血管或血管外疾病， 疾病

Large conductance, Ca2+-activated K+ channels (MaxiK, BK) are key regulators of a plethora of cell functions including vascular tone, neuronal function, and immunity. As such, knowing their natural maturation steps from synthesis to the establishment of interactions with proteins that guide them to their functional sites is key to understand the basis of their function. Thus, the long-term goal of this research is to identify the regulatory mechanisms of MaxiK channel transcription, co(post)-translational modifications, and traffic that determine its availability and function at the right time and place. We have learned about the molecular composition of MaxiK channels in different systems, their role in animal physiology by means of silencing subunit genes, and have started to grasp information on the mechanisms of their cellular traffic and on their potential networks. We will now test the general hypothesis that, MaxiK's pore-forming a subunit (Slo) gene and protein have intrinsic sequences that rule their expression, vectorial traffic, and protein-lipid interactions localizing them in strategic cell compartments according to physiological needs. Our preliminary data indicate that: i. mSlo promoter region responds to estrogen (E2) and contains potential hormone-response sequences that may rule channel expression by E2; ii. basolateral MaxiK targeting may be driven by a Slo splice variant insert; and iii.Slo can be myristoylated. We will use a multidisciplinary approach, in particular, avidin-Slo constructs for visualization of single-molecule movements with quantum dots and high resolution confocal microscopy. Specific Aims are to: 1) map the transcription start site(s) and functional E2-regulatory sequences in Slo promoter(s), and define the genomic mechanism(s) of E2-mediated regulation of Slo transcription; 2) investigate the role of Slo splice variant(s) in determining differential trafficking and targeting; and 3) investigate the mechanism and site of MaxiK myristoylation and its functional consequences. These studies should provide new information on the mechanisms that regulate MaxiK channel gene and protein expression and targeting, and identify new therapeutic pathways to alleviate cardio- or cerebro-vascular diseases.