Biological And Biochemical Characterization Of Sigma Receptors

自从我在NIDA IRP的实验室于1982年发现sigma-1受体(Sig-1R)以来的几年里，许多临床前研究表明Sig-1RS及其相关配体与中风、健忘症、抑郁症、癌症、阿尔茨海默氏病、疼痛和精神刺激剂成瘾有关。我们在这里发现，Sig-1Rs位于细胞内的一个叫做内质网(ER)的细胞器中，负责细胞中大多数蛋白质的合成。更具体地说，sig-1Rs定位于内质网膜上的一个特定亚域，该亚域直接面对并接触另一个称为线粒体的细胞内细胞器，线粒体为细胞产生能量。因此，SIG-1RS在细胞中发挥着非常重要的作用，它直接将蛋白质合成机制的健康状况与细胞中产生能量的器官联系起来。例如，Sig-1Rs调节内质网和线粒体之间的钙转移和脂肪代谢，因此参与了许多对生命系统的正常运作至关重要的细胞过程。由于Sig-1Rs是分子伴侣，通过将蛋白质维持在适当的三维构型来调节蛋白质的功能，我们正在研究除了我们迄今发现的IP3受体之外，哪些蛋白质可能由Sig-1Rs伴侣。通过这样做，我们可能会更好地理解这种分子伴侣SIG-1R如何在如此多的疾病中发挥作用。在本财政年度，我们发现Sig-1R可以在细胞内细胞器之间转运，并调节细胞内和质膜上的信号转导。在质膜上，Sig-1R作为一种“沉默的”启动子与离子通道或受体结合，等待细胞外配体或蛋白质的到来，以调节激活的离子通道或受体的作用。我们认为，SIG-1R的这种独特作用可能解释了SIG-1R与某些疾病的关系，包括对可卡因的上瘾。

In the years since my laboratory at the NIDA IRP identified the sigma-1 receptor (Sig-1R) in 1982, many preclinical studies have shown that Sig-1Rs and associated ligands are involved in stroke, amnesia, depression, cancer, Alzheimers disease, pain, and psychostimulant addiction. We found here that Sig-1Rs reside at an intracellular organelle called the endoplasmic reticulum (ER) that is responsible for the synthesis of most of proteins in the cell. More specifically, Sig-1Rs localize at a particular subdomain at the ER membrane that directly faces and contacts another intracellular organelle called mitochondrion which produces energy for the cell. Sig-1Rs thus play a very important role in the cell by directly communicating the well-being of the protein synthesis machinery to the energy-producing organalle in the cell. For example, Sig-1Rs regulate calcium transfer and lipid metabolism between the ER and mitochondrion and are thus involved in many cellular processes critical for the proper functioning of the living system. Inasmuch as Sig-1Rs are molecular chaperones that regulate the functionality of proteins by maintaining them at a proper three-domensional configuration, we are examining what proteins, in addition to the IP3 receptors that we have so far discovered, might be chaperoned by Sig-1Rs. In doing so, we might have a better understanding of how this molecular chaperone, the Sig-1R, may play a role in so many diseases. In this fiscal year we found that the Sig-1R can translocate between intracellular organelles and serves to modulate signal transduction inside of the cell and on the plasma membrane. On the plasma membrane, the Sig-1R serves as a "silent" primer binding to ion channels or receptors awaiting for the arrival of extracellular ligands or protein to modulate the action of the activated ion channels or receptors. We propose that this unique action of Sig-1Rs may explain the Sig-1R's involvement in certain diseases including addiction to cocaine.