MECHANISMS OF HEPATIC ELECTROLYTE TRANSPORT

正常的肝功能依赖于快速和精确的离子运动 以及其他溶质以一定的速率穿过每个细胞的质膜 大于1010离子秒-1。 离子的数量和类型都是 以分钟为单位进行调节，以满足不断变化的生理 由循环激素、底物可用性或 代谢应激 交通运输的这些动态变化直接影响 跨膜水运动和肝细胞体积。 实际上，荷尔蒙- 诱导的细胞体积增加最近被认为是 强信号，通过影响细胞调节肝功能 激酶、基因表达、胆汁形成和胞吐作用。 研究 本提案中描述的将评估耦合细胞的机制， 代谢，离子转运和细胞体积，通过解决工作 细胞内和细胞外信号调节细胞体积的假说 通过打开阳离子通道动态调节Na+流入， 选择性通道，刺激细胞体积增加，K+和Cl- 流出，刺激细胞体积减少。 具体目标是（i） 评估细胞外ATP作为自分泌/旁分泌的作用， 介导细胞肿胀恢复的信号分子; ii）评估 蛋白激酶C的生理作用和靶点， 作为细胞内信号分子的磷酸肌醇3-激酶 将细胞体积变化转导为通道调节; iii）确定 体积敏感性Cl-流出的分子基础，以及iv）识别 Na+流入和回收的通道和调控机制 细胞萎缩 通道和信号通路解决在 这些研究代表了激素和其他 利用细胞体积作为中间信号来调节 肝脏代谢和分泌功能。 此外，定义 其机制可能为肝脏疾病的治疗提供新的策略。 在细胞体积调节受损的情况下的损伤， 包括酒精中毒、局部缺血和肝脏炎症。

Normal liver function depends upon rapid and precise movement of ions and other solutes across the plasma membrane of each cell at rates greater that 1010 ions sec -1. Both the number and types of ions are regulated on a minute-to-minute basis to meet changing physiologic demands caused by circulating hormones, substrate availability, or metabolic stress. These dynamic changes in transport directly influence transmembrane water movement and liver cell volume. Indeed, hormone- induced cell volume increases have recently been recognized to be a potent signal, regulating liver function through effects on cellular kinases, gene expression, bile formation, and exocytosis. The studies described in this proposal will evaluate the mechanisms that couple cell metabolism, ion transport, and cell volume by addressing the Working Hypothesis that intra- and extracellular signals regulate cell volume through dynamic modulation of Na+ influx through opening of cation- selective channels, a stimulus for cell volume increases, and K+ and Cl- efflux, a stimulus for cell volume decreases. The Specific Aims are i) to evaluate the role of extracellular ATP as an autocrine/paracrine signaling molecule mediating recovery from cell swelling; ii) to assess the physiologic roles and targets of protein kinase C and phosphoinositide 3-kinase as intracellular signaling molecules transducing cell volume changes to channel regulation; iii) to determine the molecular basis of volume-sensitive Cl- efflux, and iv) to identify the channels and regulatory mechanisms governing Na+ influx and recovery from cell shrinkage. The channels and signaling pathways addressed in these studies represent essential sites of action for hormones and other signals that utilize cell volume as an intermediary signal to modulate liver metabolic and secretory functions. In addition, definition of the mechanisms involved may provide new strategies for treatment of liver injury under conditions where cell volume regulation is impaired, including alcohol toxicity, ischemia, and liver inflammation.