Ca/Calmodulin Activated Phospholipase A2 and Na K ATPase

描述（申请人摘要）：磷脂酶A2（PLA 2）的一种新形式 与人红细胞的细胞骨架相关的抑制Na，K-ATP酶， 在细胞活化过程中发生的细胞内游离钙浓度。 这种形式的PLA 2也可能存在于神经元中，在那里它可以介导神经元的凋亡。 细胞内钙离子对Na，K-ATP酶的影响。Na，K-ATP酶的调节 钙离子对神经元的作用与控制神经递质的释放有关 并且与双相情感障碍的发展有关。中的数据 红细胞提示单个PLA 2以两种形式存在：磷酸化和 未磷酸化。当磷酸化时，PLA 2被微摩尔（0.2-10 通过钙调蛋白（CaM）的结合来释放游离钙。在没有 在磷酸化过程中，PLA 2被毫摩尔（0.1-1 mM）钙直接活化。 这种膜相关的PLA 2具有不同于其他PLA 2的性质， 它被CaM激活，对微摩尔和毫摩尔的敏感性 钙及其对抑制剂的反应。具体目标是确定（1） Ca/CaM激活PLA 2的分子基础;（2）Ca/CaM激活PLA 2的机制 影响Na，K-ATP酶。结果将定义新的Ca/CaM-PLA 2，其能够 参与细胞信号传导和调节Na，K-ATP酶， 改变细胞内游离钙。这些研究将以红色进行 细胞由于其作为一个简单的模型系统的优势，但应该 适用于其他细胞，包括神经元，其中Na，K-ATP酶也是 受细胞内游离钙变化的抑制。

DESCRIPTION (Applicant's abstract): A new form of phospholipase A2 (PLA2) associated with the cytoskeleton of human red cells inhibits Na,K-ATPase at the concentrations of intracellular free calcium that occur during cell activation. This form of PLA2 may also be present in neurons, where it could mediate the effects of intracellular calcium on Na,K-ATPase. Regulation of Na,K-ATPase in neurons by calcium has been linked to the control of neurotransmitter release and has been implicated in the development of bipolar disorders. The data in red cells suggest a single PLA2 that exists in two forms: phosphorylated and unphosphorylated. When phosphorylated, PLA2 is activated by micromolar (0.2-10 uM) free calcium by the binding of calmodulin (CaM). In the absence of phosphorylation, PLA2 is directly activated my millimolar (0.1-1 mM) calcium. This membrane-associated PLA2 has properties distinct from other PLA2s based on its activation by CaM, its sensitivity to both micromolar and millimolar calcium, and its response to inhibitors. The specific aims are to determine (1) the molecular basis for the Ca/CaM stimulated PLA2 and (2) how the Ca/CaM PLA2 affects the Na,K-ATPase. The results will define a new Ca/CaM-PLA2 capable of participating in cell signaling and of regulating Na,K-ATPase in response to changes intracellular free calcium. The studies will be carried out in red cells due to their advantages as a simple model system, but should be applicable to other cells, including neurons, where Na,K-ATPase is also inhibited by changes in intracellular free calcium.