Inositol 1,4,5-trisphosphate response threshold

性状（由申请方提供）：1，4，5-三磷酸肌醇（InsP3） 其受体（InsP3R）的连接导致细胞内储存的 钙这种钙库消耗与随后的钙内流通过 钙库操纵钙电流Icrac。钙，来源于细胞内 通过Icrac储存释放和流入，调节了一个非常多样化的 细胞过程，包括生长、分化、死亡和急性 免疫系统细胞对抗原的效应子应答。InsP3水平与 控制，钙释放和内流反应可以分离， 它们对胞质InsP3水平的不同敏感性。调制 用于治疗目的的这些钙信号可以通过 操纵他们这一代的门槛。 在这里，我们建议调查的机制，设置响应阈值 用于InsP3驱动的钙释放和内流。我们假设， InsP3R的性质，以及由酶提供的环境， 代谢InsP3，可能是特定活性的关键决定因素， InsP3的浓度。此外，我们还将研究 这些因素对特定的钙储存亚室的产生， 不同的反应阈值，如钙储存耦合到Icrac 激活（CRAC存储）。这个车厢以其低矮的 灵敏度（即，高阈值）至InsP3。最后，我们将探讨 Ins（1，4，5）P3以外的磷酸肌醇控制 免疫系统细胞中的钙释放和内流反应。

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 subcompartments 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. Finally, we will explore the biology of phosphoinositides other than Ins (1,4,5) P3 in the control of calcium release and influx responses in immune system cells.