RECEPTOR REGULATED CALCIUM ENTRY IN EXOCRINE SECRETION

了解链接激活的步骤中涉及的细节 细胞表面受体与细胞的启动和控制 包括生长和分化在内的功能是一个根本问题 在各种重要的过程中都有影响，包括 临床情况。其中许多激活途径的一个关键特征 细胞内钙离子的升高至少部分是由于 促进细胞外培养上清液中的钙离子进入。这些步骤 对这一途径的激活负有责任的人目前尚不清楚。 到目前为止，关于这类机制的辩论主要集中在 使[钙]持续升高的条件。现在是时候了 已知在更多的生理条件下[钙]反应 经常涉及更复杂的变化，包括振荡波 和空间上局部的[Ca~(2+)]升高(所谓的‘触发区’) CA2+进入通常被认为只在 这样的反应，但我们最近的数据表明，情况并非如此。证据 进一步表明，目前解释钙离子控制的模型 持续升高[Ca~(2+)]的进入不足以 解释了我们在这些过程中观察到的钙离子进入的特征 更复杂的[钙]反应。这种复杂的[钙]信号是 现在被认为在适当的激活中具有至关重要的作用 有效的外分泌液和蛋白质所必需的机制 腺泡细胞的分泌物。我们的目的是研究钙离子的作用 进入[钙]振荡和[钙]触发区和 控制它的机制。细胞的数字荧光成像将 被用来获取关于 [Ca~(2+)]反应和Ca~(2+)进入。此外，合并后 光计数显微荧光法膜片钳制和闪光光解 将用于高时间分辨率的{Ca2+]响应和 它们与膜电位的关系及其与细胞外信号转导的关系 膜电流。试析钙离子内流的性质和作用 在如此复杂的反应中将极大地促进我们对 细胞内的信号通路。它还可能允许开发 可以用来操纵或改变这一点的药理药剂 基础的和广泛分布的临床相关过程。

Understanding of the details involved in the steps linking activation of receptors on the cell surface with the initiation and control of cell function including growth and differentiation is a fundamental question with implications in a wide variety of improtant processes including clinical situations. A key feature of many of these activation pathways is an elevation of intracellular Ca2+ resulting at least in part from an enhanced entry of Ca2+ from the extracellular medium. The steps responsible for the ectivation of this pathway are presently unknown. To date debate on such mechanisms has focussed on responses under conditions generating a sustained elevation in [Ca2+]. It is now known that under more physiological conditions [Ca2+] responses frequently involve more complex changes including oscillations waves and spatially localized increases in [Ca2+] (so-called 'trigger zones') Ca2+ entry has generally been assumed to play only a minor role in such responses but our recent data suggest this is not so. The evidence further suggests that current models explaining the control of Ca2+ entry during a sustained elevation of [Ca2+] are not adequate to account for the features we have observed for Ca2+ entry during these more complex [Ca2+] responses. Such complex [Ca2+] signals are now believed to be of critical importance in the appropriate activation of mechanisms essential for effective exocrine fluid and protein secretion in acinar cells. Our aim is to investigate the role of Ca2+ entry in [Ca2+] oscillations and [Ca2+] trigger zones and the mechanisms controlling it. Digital fluorescence imaging of cells will be employed to obtain spatial information on the relationships between [Ca2+] responses and Ca2+ entry. In addition combined photoncounting microfluorimetry patch-clampong and flash-photolysis will be used for high temporal resolution of {cA2+] responses and their relationships with membrane potential and the activation of membrane currents. Analysis of the nature and roles of Ca2+ entry in such complex responses will significantly further our understanding of signalling pathways in cells. It may also permit the development of pharmacological agents that can be used to manipulate or modify this funddamental and widely distributed process in clinically relevant ways.