RECEPTOR REGULATED CALCIUM ENTRY IN EXOCRINE SECRETION

描述（改编自申请人的描述）：许多激素和 神经递质通过提高细胞内的 浓度的游离Ca2+（[Ca2+]），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+]的关键特征 信号是增强的Ca 2+从细胞外介质进入， 在塑造细胞的整体Ca2+信号中起关键作用。的性质和 对这种增强的Ca2+进入的控制仍然存在争议，特别是， 发生在典型的空间和时间复杂的[Ca2+]信号期间， 刺激的生理条件。这项研究的长期目标是 了解分子基础，调节机制和生理 这是Ca2+的作用。虽然目前这种进入模式的重点是 所谓的“容量”（或存储操作）机制， 某些细胞内Ca2+储存足以激活进入，证据 表明这可能不会在复杂的[Ca2+]信号中起作用， 生理刺激水平。相反，我们最近发现了一个 独特的，非容量性的Ca2+进入途径，似乎是特异性的 负责在这些类型的反应中进入Ca2+。这本小说 途径受受体介导的花生四烯酸生成的调节 涉及一种钙离子选择性通道， 由能力机制激活。我们建议将 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 [Ca2+]在生理刺激水平下产生的信号。重要的是， 的空间和时间特征的复杂[Ca2+]信号下产生的 已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。这个新的 确定的[Ca2+]进入途径在这些信号的调制 表明它可能具有相当大的生理意义， 也是未来药理学操作的重要潜在靶点， 临床相关方法

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.