RECEPTOR REGULATED CALCIUM ENTRY IN EXOCRINE SECRETION

描述(根据申请者的描述改编)：多种激素和 神经递质通过提高细胞内的 游离钙浓度([Ca~(2+)])，从而诱导适当的 调节多种细胞活动，包括分泌、运动、 生长、基因转录和分化。这些[Ca2+]的一个关键特征 信号是细胞外介质中钙离子的增强进入，它发挥着 在细胞整体钙信号的形成中起着关键作用。自然界和 对这种增强的钙离子进入的控制仍然存在争议，特别是 发生在空间和时间上复杂的[Ca2+]信号期间 刺激的生理条件。这项研究的长期目标是 了解其分子基础、调控机制和生理机制 这个钙离子条目的作用。尽管当前针对此类条目的模型主要集中在 所谓的“容量”(或商店操作的)机制，其中清空 证据表明，某些细胞内的钙离子存储足以激活进入 这表明这可能不是在复杂的[Ca~(2+)]信号期间运行的 生理水平的刺激。相反，我们最近发现了一个 独特的，非容量性的钙离子进入途径，似乎是特异性的 负责在这些类型的反应中钙离子的进入。这部小说 受体介导的花生四烯酸合成途径的调控 涉及一种与那些完全不同的钙选择性通道 由容能机制激活。我们建议将其描述为 所涉及的通道的生物物理性质，负责的生化途径 它的激活，以及它在塑造和调节人类社会发展中所起的作用(S [Ca~(2+)]信号产生于生理刺激水平。重要的是 大鼠脑内钙离子信号的时空分布特征 众所周知，这些条件对于适当的和有针对性的 激活特定的细胞活动。这一新的关键作用 确定的[Ca~(2+)]进入途径在这些信号的调制中起作用 表明它可能具有相当大的生理意义， 也是未来药理操作的重要潜在靶点 临床上相关的方法。

DESCRIPTION (Adapted from applicant's Description): Many hormones and neurotransmitters exert their effects on cells by raising the intracellular concentration of free Ca2+ ([Ca2+]), thereby inducing the appropriate modulation of a variety of cellular activities including secretion, motility, growth, gene transcription, and differentiation. A key feature of these [Ca2+] signals is an enhanced entry of Ca2+ from the extracellular medium, which plays a pivotal role in shaping the overall Ca2+ signals of cells. The nature and control of this enhanced Ca2+ entry remain controversial, particularly that occurring during the spatially and temporally complex [Ca2+] signals typical of physiological conditions of stimulation. The long-term goal of this research is to understand the molecular basis, mechanism of regulation, and physiological roles of this Ca2+ entry. Although current models for such entry focus on the so-called "capacitative" (or store-operated) mechanism where the emptying of certain intracellular Ca2+ stores is sufficient to activate entry, evidence suggests this may not operate during the complex [Ca2+] signals seen at physiological levels of stimulation. Instead we have recently identified a distinct, noncapacitative Ca2+ entry pathway which appears to be specifically responsible for the entry of Ca2+ during these types of response. This novel pathway is regulated by the receptor-mediated generation of arachidonic acid and involved a Ca2+-selective channel that is entirely distinct from those activated by the capacitative mechanism. We propose to characterize the biophysical nature of the channel involved, the biochemical pathway responsible for its activation, and the role(s) that it plays in shaping and modulating the [Ca2+] signals generated at physiological levels of stimulation. Importantly, the spatial and temporal features of the complex [Ca2+] signals generated under these conditions are known to be critical for the appropriate and targeted activation of specific cellular activities. The key role that this newly identified [Ca2+] entry pathway has in the modulation of these signals indicates that it is likely to be of considerable physiological significance, and an important potential target for future pharmacological manipulation in clinically relevant ways.