Biological And Biochemical Characterization Of Sigma Receptors

自从1982年我在NIDA IRP的实验室发现了sigma-1受体（Sig-1R）以来，许多临床前研究表明，Sig-1R及其相关配体与中风、健忘症、抑郁症、癌症、阿尔茨海默病、疼痛和精神兴奋剂成瘾有关。我们在这里发现，sig1rs存在于一种称为内质网（ER）的胞内细胞器中，该细胞器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传达给细胞中的能量产生器官。例如，Sig-1Rs调节内质网和线粒体之间的钙转移和脂质代谢，因此参与许多对生命系统正常运作至关重要的细胞过程。由于Sig-1Rs是分子伴侣，通过维持蛋白质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，哪些蛋白质可能被Sig-1Rs所陪伴。这样做，我们可能会更好地了解这种分子伴侣，sig1r，是如何在许多疾病中发挥作用的。在本财年，我们发现Sig-1R可以在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作为结合离子通道或受体的“沉默”引物，等待细胞外配体或蛋白质的到来，以调节活化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参与某些疾病，包括可卡因成瘾。

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.