Inositol (1,4,5) trisphoshate response thresholds

描述（由申请方提供）：1，4，5-三磷酸肌醇（InsP 3）与其受体（InsP 3R）的连接导致储存的细胞内钙释放。这种钙池消耗通过钙池操作的钙电流ICRAC与随后的钙内流耦合。钙来自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、死亡和免疫系统细胞对抗原的急性效应器反应。InsP 3水平受到严格控制，钙释放和内流反应可以通过其对胞质InsP 3水平的差异敏感性来分离。用于治疗目的的这些钙信号中的任一种的调节可以通过操纵其产生的阈值来实现。 在这里，我们建议调查的机制，设置响应阈值InsP 3驱动的钙释放和流入。我们假设InsP 3R的固有特性和代谢InsP 3的酶所提供的环境可能是给定浓度InsP 3的比活性的关键决定因素。此外，我们将研究这些因素对产生具有不同响应阈值的特定钙储存子室的贡献，例如与ICRAC激活（“CRAC储存”）耦合的钙储存。该隔室以其低灵敏度（即，高阈值）至InsP 3。

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.