Inositol (1,4,5) trisphoshate response thresholds

描述（由申请人提供）：肌醇1,4,5-三磷酸（InsP3）与其受体（InsP3R）的连接导致细胞内储存钙的释放。这种储存量耗竭通过储存量操作的钙电流ICRAC与随后的钙流入相耦合。钙来源于细胞内的储存释放和通过ICRAC的内流，调节着一系列不同的细胞过程，包括生长、分化、死亡和免疫系统细胞对抗原的急性效应反应。InsP3水平受到严格控制，钙释放和内流反应可以通过它们对胞浆中InsP3水平的不同敏感性来解离。调节这些钙信号中的任何一种用于治疗目的，可以通过操纵它们产生的阈值来实现。

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.