REGULATION OF INTRACELLULAR CALCIUM IN RENAL CELLS

描述(改编自申请人的摘要)： 感官细胞中的机械感知和转导早已为人所知。 近年来，机械应力已变得明显 (细胞膨胀、膜拉伸、剪切应力产生的渗透机械应力) 在非感觉细胞中可以在调节众多细胞方面发挥主要作用 包括钙内流在内的过程，因此，钙信号传导。在肾中 细胞，生理和病理生理产生的机械应力 已知状态通过所谓的钙离子通道激活钙离子内流，如 钙通道阻滞剂(例如：钙通道阻滞剂)可以消除这种内流。 二氢吡啶类、L类钙通道阻滞剂)。最近他们 发现了一种新的DHP敏感的钙通道(钙选择性)。 似乎起中心作用的兔近端小管细胞的边界 在机械诱导的钙信号状态下。该通道被激活 通过细胞肿胀和膜拉伸。它似乎受到了监管 间接通过对磷脂酰肌醇的机械敏感调节 蛋白激酶C的水解(磷脂酶C-b)和激活类似于 这是最近在心肌细胞中发现的L型钙通道。这个 该项目的总体目标是确定功能、规则和 这一新渠道的结构有以下四个具体目标：1) 确定DHP敏感的钙通道在调节中的作用 机械应激过程中细胞内钙水平与钙信号转导 状态(渗透机械、膜拉伸)；2)表征通道 DHP敏感钙离子的特性(单通道电流和全细胞电流) 以及机械应力对这些特性的影响；3) 刻画机械转导途径(S)调节 DHP敏感的钙通道；4)确定细胞的分子同一性。 近端肾小管细胞对DHP敏感的钙通道。该项目将拥有 机械应力在控制多个 钙依赖在健康和疾病中的作用。

DESCRIPTION (Adapted from the Applicant's Abstract): The importance of mechanical sensing and transduction in sensory cells has long been known. In recent years it has become evident that mechanical stresses (osmo-mechanical stress from cell swelling, membrane stretch, shear stress) in non-sensory cells can play a major role in regulating numerous cell processes including calcium influx and, hence, Ca+ signaling. In kidney cells, mechanical stresses generated by physiological and pathophysiological states are known to activate Ca+ influx through purported Ca+ channels as the influx can be abolished by calcium channel blockers (e.g. Dihydropyridines (DHP), L-type Ca+ channel blocker). Recently they identified a novel DHP-sensitive Ca+ channel (Ca+-selective) on the apical border of rabbit proximal tubule cells that appears to play a central role in mechanically-induced states of Ca+ signaling. The channel is activated by cell swelling and membrane stretch. It appears to be regulated indirectly via mechano-sensitive regulation of phosphatidyl inositol hydrolysis (phospholipase C-b) andactivation of protein kinase C similar to that recently identified for L-type Ca+ channels in cardiac myocytes. The overall goal of the project is to characterize the function, regulation and structure of this novel channel with the following four Specific Aims: 1) To determine the role of the DHP-sensitive Ca+ channel in regulating intracellular calcium levels and Ca+ signaling during mechanically-stressed states (osmo-mechanical, membrane stretch); 2) To characterize the channel properties (single channel and whole cell currents) of the DHP-sensitive Ca+ channel and the effect of mechanical stresses on these properties; 3) To characterize the mechano-transduction pathway(s) regulating the DHP-sensitive Ca+ channel; and 4) To determine the molecular identity of the DHP-sensitive Ca+ channel in proximal tubule cells. The project will have broad implications to the role of mechanical stress in controlling numerous Ca-dependent functions in health and disease.