Control of IP3R-Mediated Calcium Release

IP3R 介导的钙释放的控制

• 批准号: 8881893
• 负责人: SUI RONG WAYNE CHEN
• 金额: $ 43.44万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881893
• 关键词: Address; Affinity; Binding; Binding Sites; Buffers; Calcium; Calcium Signaling; Cardiac; Cations; Cell physiology; Cells; Charge; Dependence; Deposition; Divalent Cations; Elements; Endoplasmic Reticulum; Failure; Feedback; Health; Human; ITPR1 gene; Image; Inositol; Kinetics; Knowledge; Laboratories; Link; Measures; Mediating; Membrane; Molecular; Mutate; Nature; Outcome; Physiological; Process; Recombinants; Regulation; Relative (related person); Resources; Ryanodine Receptor Calcium Release Channel; Side; Signal Transduction; Site; Skeletal Muscle; Source; Specific qualifier value; Testing; Therapeutic Intervention; Time; Tissues; Work; base; cell type; defined contribution; familial Alzheimer disease; feeding; gain of function; interest; multidisciplinary; mutant; novel; operation; public health relevance; receptor

 DESCRIPTION (provided by applicant): Intracellular Ca2+ signals govern numerous physiological phenomena. Often these signals are generated by opening of ryanodine receptor (RyR) or inositol trisphosphate receptor (IP3R) Ca2+ release channels on the endoplasmic reticulum (ER) membrane. In tissues where one of these channels dominates, functional cross talk with the other is often present. Such cross talk between Ca2+ release channels has been documented in smooth, cardiac and recently skeletal muscle. In other words, function of each has ramifications on both. Here, our focus is the local Ca2+ control of the type-1 IP3R. IP3R-mediated Ca2+ release is controlled by the concerted actions of local IP3 and Ca2+. The IP3-control signal (source, size, kinetics) is fairly well defined. In contrast, the Ca2+-control signa is poorly understood because of its multi-modal nature. The Ca2+ control signal modes include cytosolic Ca2+ activation, cytosolic Ca2+ inactivation, intra-ER Ca2+ regulation (luminal regulation), auto-FT (Feed Through) and inter-FT Ca2+ regulation. Each has been explored separately but never have all been defined as a whole. The ill-defined local multi-modal Ca2+ control of the IP3R is a significant obstacle that has limited our understanding of both IP3R hierarchical Ca2+ signaling (channel to puff to wave) and "quantal" Ca2+ release. The least understood Ca2+ control modes are auto-FT, inter-FT and intra-ER Ca2+ regulation. Often, their existence (let alone significance) has been questioned due to the lack of definitive information (as the overlapping signals and feedback-loops have precluded separate testing of variables). This obstacle is overcome here and multi- modal IP3R local Ca2+ control defined as a whole for the first time. This is significant because IP3R governs Ca2+ signaling in nearly all cells and its abnormal function can have lethal ramifications. This means IP3R local control mechanisms are both potential points of pathological failure and logical targets for therapeutic intervention, making knowledge of their molecular basis highly significant to human health. Here, 3 laboratories with unique complementary resources and expertise combine to address the hypothesis: Multi-modal IP3R local Ca2+ control (activation, inactivation & feed through) includes a luminal intra-pore Ca2+-Mg2+ sensing site that governs the channel's IP3 sensitivity, the latter newly discovered mechanism explains IP3R-mediated quantal Ca2+ release in cells. This proposal applies a multidisciplinary (molecular to cellular) carefully crafted approach to tes this hypothesis. The specific aims are to 1) define multi-modal local Ca2+ control of type-1 IP3R function and 2) identify the molecular basis of quantal type-1 IP3R Ca2+ release. This work will establish the biophysical basis of multi-modal local Ca2+ control of single IP3R1 function and likely will identify a novel (and long sought) single IP3R molecular mechanism that explains quantal release. This will represent a significant advancement in our understanding of IP3R1 local control.

 描述（由申请人提供）：细胞内Ca 2+信号控制许多生理现象。这些信号通常是通过打开内质网（ER）膜上的兰尼碱受体（RyR）或三磷酸肌醇受体（IP 3R）Ca 2+释放通道产生的。在这些通道之一占主导地位的组织中，通常存在与另一个通道的功能性串扰。在平滑肌、心肌和最近的骨骼肌中已经记录了Ca 2+释放通道之间的这种串扰。换句话说，每一个的功能都对两者产生影响。在这里，我们的重点是1型IP 3R的局部Ca 2+控制。 IP 3R介导的Ca 2+释放受局部IP 3和Ca 2+的协同作用控制。IP 3对照信号（来源、大小、动力学）定义相当明确。相比之下，Ca 2 +-控制信号由于其多模态性质而知之甚少。Ca ~（2+）调控信号模式包括胞浆Ca ~（2+）激活、胞浆Ca ~（2+）失活、内质网内Ca ~（2+）调节（管腔调节）、自动-FT（馈通）和FT间Ca ~（2+）调节。每一个都被单独探讨过，但从来没有被定义为一个整体。 IP 3R的不明确的局部多模态Ca 2+控制是一个重大障碍，限制了我们对IP 3R分层Ca 2+信号传导（通道到喷流到波）和“量子”Ca 2+释放的理解。最不了解的Ca 2+控制模式是自动FT、FT间和ER内Ca 2+调节。通常，由于缺乏明确的信息（重叠的信号和反馈回路排除了变量的单独测试），它们的存在（更不用说重要性）受到质疑。本文克服了这一障碍，首次将多模态IP 3R局部Ca ~（2+）控制定义为一个整体。这是重要的，因为IP 3R在几乎所有细胞中控制Ca 2+信号传导，其异常功能可能具有致命的后果。这意味着IP 3R局部控制机制既是病理失败的潜在点，也是治疗干预的逻辑靶点，因此了解其分子基础对人类健康具有重要意义。 在这里，3个具有独特互补资源和专业知识的实验室联合收割机来解决这一假设：多模式IP 3R局部Ca 2+控制（激活，失活和馈通）包括一个管腔内孔Ca 2 +-Mg 2+传感位点，该位点控制通道的IP 3敏感性，后一种新发现的机制解释了IP 3R介导的细胞中的量子Ca 2+释放。这项建议采用了多学科（分子到细胞）精心制作的方法来测试这一假设。具体目标是1）定义1型IP 3R功能的多模式局部Ca 2+控制和2）鉴定量子1型IP 3R Ca 2+释放的分子基础。 这项工作将建立单一IP 3R 1功能的多模式局部Ca 2+控制的生物物理学基础，并可能确定一种新的（和长期寻求的）单一IP 3R分子机制，解释量子释放。这将代表我们对IP 3R 1本地控制的理解的重大进步。