Inositol (1,4,5) trisphoshate response thresholds

肌醇（1,4,5）三磷酸反应阈值

• 批准号: 7190550
• 负责人: REINHOLD PENNER
• 金额: $ 36.27万
• 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/7190550
• 关键词: Acute; Affinity; Antigens; B-Lymphocytes; Binding; Biochemical; Calcium; Calcium Channel; Calcium Signaling; Cell membrane; Cell physiology; Cells; Cessation of life; Complement; Condition; Coupled; Couples; Differentiation and Growth; Disruption; Environment; Enzymes; Exhibits; Generations; Genes; Homeostasis; Immune system; Inositol; Inositol 1,4,5-Trisphosphate; Inositol Phosphates; Investigation; Ligation; Lipids; Location; Molecular; Phosphoric Monoester Hydrolases; Phosphotransferases; Polyphosphates; Property; Protein Isoforms; Purpose; Range; Specificity; System; Therapeutic; base; inositol 4,5-bisphosphate; receptor; response; therapeutic target

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(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。这种存储耗尽通过商店运营的钙电流ICRAC与随后的钙内流相耦合。钙来源于细胞内储存的释放和通过ICRAC的内流，调节着一系列非常不同的细胞过程，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InsP3水平的不同敏感性来分离。为了治疗的目的，这些钙信号中的任何一个的调节可以通过控制它们产生的阈值来实现。 在这里，我们建议研究为InsP3驱动的钙释放和内流设定反应阈值的机制。我们推测，InsP3R的固有特性以及代谢InsP3的酶所提供的环境可能是特定浓度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库亚室的产生的贡献，例如与ICRAC激活偶联的钙库(CRAC库)。值得注意的是，该隔室对InsP3的敏感性较低(即阈值较高)。