BIOLOGICAL AND BIOCHEMICAL CHARACTERIZATION OF SIGMA RECEPTORS

这个项目描述了生物化学和药理学的特性 西格玛受体和配体。我们发现了一种蛋白质 类似于阿片/西格玛受体，并继续作用于其最终 净化。我们使用肝素的结果是一个强有力的没有竞争力的 Sigma受体抑制物提示Sigma受体与 到细胞内钙动员。一项单独的实验， 丹曲林已经表明，部分钙流出来自 细胞内的内质网不受游离的控制 细胞内钙离子浓度。我们开始做好准备 利用共聚焦显微镜进一步研究Sigma受体的作用 在细胞内钙动员的调节中。 在行为层面上，除了表明084-a之前 在NIDA IRP-发现的选择性Sigma配体可以逆转 快速老化小鼠遗传的学习记忆障碍 (山姆)，我们现在已经获得了证据表明084之前的版本逆转了测试版- 淀粉样蛋白(25-35)致小鼠认知功能障碍。的这一属性 有趣的是，Pre-084与神经类固醇DHEAS和 孕烯醇酮硫酸盐，已被证明在西格玛有活性 感受器。此外，孕酮-具有纳米分子的西格玛配体 亲和力，拮抗了这三种物质改善记忆的特性 化合物。

This projects delineates biochemical and pharmacological properties of sigma receptors and ligands. We have discovered a protein which resembles the opioid/sigma receptors and continued to work on its final purification. Our results with heparin being a potent uncompetitive inhibitor at sigma receptors suggest that sigma receptors are related to intracellular calcium mobilization. A separate experiment with dantrolene have indicated that a portion of the calcium efflux from the endoplasmic reticulum in the cells is not under the control of the free intracellular calcium concentration. We are beginning to get ready to use confocal microscope to further examine the role of sigma receptors in the regulation of intracellular calcium mobilization. On the behavioral level, in addition to showing that PRE-084 - a selective sigma ligand discovered at the NIDA IRP - could reverse the learning and memory deficit inherited in senescence accelerated mouse (SAM), we have now obtained evidence that PRE-084 reversed the beta- amyloid(25-35)-induced cognitive deficit in mouse. This property of PRE-084, interestingly, is shared by neurosteroids DHEAS and pregnenolone sulfate which have been shown to be active at sigma receptors. Further, progesterone - a sigma ligand with nanomolar affinity, antagonized the memory-improving properties of all three compounds.