Inositol (1,4,5) trisphoshate response thresholds

肌醇（1,4,5）三磷酸反应阈值

• 批准号: 6868963
• 负责人: REINHOLD PENNER
• 金额: $ 38.25万
• 依托单位: QUEEN'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868963
• 关键词: B lymphocyte; biological signal transduction; calcium flux; cell membrane; cell surface receptors; cytoplasm; endoplasmic reticulum; enzyme activity; enzyme mechanism; inositol phosphates; intracellular; northern blottings; phosphorylation; polymerase chain reaction; protein isoforms

DESCRIPTION (provided by applicant): Inositol 1,4,5-trisphosphate (InsP3) ligation of its receptor (InsP3R) results in release of stored intracellular calcium. This store-depletion couples to subsequent calcium influx via the store-operated calcium current ICRAC. Calcium, derived from both intracellular store release and influx via ICRAC, regulates a remarkably diverse range of cellular processes including growth, differentiation, death, and the acute effector responses of immune system cells to antigen. InsP3 levels are tightly controlled, and calcium release and influx responses can be dissociated by their differential sensitivity to cytosolic InsP3 levels. Modulation of either of these calcium signals for therapeutic purposes may be achieved via manipulation of the threshold for their generation. Here we propose to investigate the mechanisms that set the response threshold for InsP3- driven calcium release and influx. We hypothesize that both intrinsic properties of the InsP3R, and the environment provided by enzymes that metabolize InsP3, may be critical determinants of the specific activity of a given concentration of InsP3. Moreover, we will investigate the contribution of these factors to the generation of specific calcium-store sub-compartments with different response thresholds, such as the calcium store that couples to ICRAC activation (the 'CRAC store'). This compartment is notable for its low sensitivity (i.e., high threshold) to InsP3.

描述（由申请人提供）：肌醇1,4,5-三磷酸（InsP3）与其受体（InsP3R）的连接导致储存的细胞内钙的释放。这种存储耗尽与随后的钙流入通过存储操作的钙电流 ICRAC 耦合。钙来源于细胞内储存释放和通过 ICRAC 流入，调节多种细胞过程，包括生长、分化、死亡以及免疫系统细胞对抗原的急性效应反应。 InsP3 水平受到严格控制，钙释放和流入反应可以通过它们对胞质 InsP3 水平的不同敏感性来分离。出于治疗目的调节这些钙信号中的任一个可以通过操纵其产生的阈值来实现。 在这里，我们建议研究为 InsP3 驱动的钙释放和流入设定响应阈值的机制。我们假设 InsP3R 的内在特性和代谢 InsP3 的酶提供的环境可能是给定浓度的 InsP3 比活性的关键决定因素。此外，我们将研究这些因素对具有不同反应阈值的特定钙储存子区室的生成的贡献，例如与 ICRAC 激活耦合的钙储存（“CRAC 储存”）。该区室以其对 InsP3 的低敏感性（即高阈值）而闻名。