Calcium Release - Activated Calcium Current Icrac

钙释放 - 活化钙电流 Icrac

• 批准号: 56850204
• 负责人: Dr. Annette Johanna Lis
• 金额: --
• 依托单位: Fachrichtung Biophysik
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2008-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/56850204?language=en
• 关键词: Calcium; Release; Activated; Current; Icrac

The prototypical store-operated calcium-influx pathway ICRAC (for “calcium-release activated calcium current”) originally was identified in Prof. Penner laboratory in 19921. Since then this lab, and others have acquired substantial information about ICRAC’s physiological and clinical importance, however, the molecular composition of the CRAC channels has remained elusive2. Only recently did a significant finding establish that a protein called stromal interaction molecule (STIM1), acting as the sensor for store Ca2+ content, is required for functional store-operated Ca2+ influx3, 4. This exciting finding was followed by the identification of another essential protein for store-operated calcium entry called CRAC Modulator 1 (CRACM1) by our group5 and Orai1 by an independent study from the Rao and Lewis laboratories6. Suppression of this protein by RNAi abolishes CRAC channel activity, as does a point mutation of CRACM1 in lymphocytes of some patients suffering from Severe Combined Immune Deficiency (SCID). The combined overexpression of STIM1 and CRACM1 greatly amplifies store-operated currents and these currents possess the most defining characteristics of ICRAC 7. Work from three laboratories (Cahalan, Rao, and our group) identified amino acids in transmembrane and loop domains of CRACM1 that affect ion selectivity, demonstrating that CRACM1 represents a pore-forming subunit of the CRAC channel. My data show that the CRACM1 homologs CRACM2 and CRACM38 also form store-operated channels with distinct properties. My proposal focuses on CRACM1 and its homologs, as a group of proteins that mediate store-operated Ca2+ entry with distinct functional properties. I propose biophysical, molecular and functional approaches to investigate the structural and mechanistic aspects of these proteins and their roles in store-operated Ca2+ entry.

典型的钙池操纵的钙内流途径ICRAC（“钙释放激活钙电流”）最初于1992年在Penner教授实验室发现1。从那时起，该实验室和其他实验室已经获得了关于ICRAC生理和临床重要性的大量信息，然而，CRAC通道的分子组成仍然不清楚2。直到最近才有一项重要的发现，即一种称为基质相互作用分子（STIM 1）的蛋白质，作为钙离子含量的传感器，是功能性钙离子库操作的钙离子流入所必需的3，4。这一令人兴奋的发现之后，我们的小组5和Rao和刘易斯实验室的一项独立研究6分别鉴定了另一种钙库操纵钙进入的必需蛋白质，称为CRAC调节剂1（CRACM 1）和Orai 1。通过RNAi抑制这种蛋白质消除了CRAC通道活性，就像一些患有严重联合免疫缺陷（SCID）的患者的淋巴细胞中CRACM 1的点突变一样。STIM 1和CRACM 1的组合过表达极大地放大了存储操作的电流，并且这些电流具有ICRAC 7的最确定的特征。来自三个实验室（Cahalan，Rao和我们的小组）的工作确定了CRACM 1跨膜和环结构域中影响离子选择性的氨基酸，表明CRACM 1代表CRAC通道的成孔亚基。我的数据显示，CRACM 1同源物CRACM 2和CRACM 38也形成具有不同性质的商店操作通道。我的建议集中在CRACM 1及其同源物，作为一组蛋白质，介导存储操作的Ca2+进入具有不同的功能特性。我建议生物物理，分子和功能的方法来研究这些蛋白质的结构和机制方面，以及它们在存储操作的Ca2+进入的作用。