Biological And Biochemical Characterization Of Sigma Receptors

Sigma 受体的生物学和生化特征

• 批准号: 8933803
• 负责人: Tsung-Ping Ping Su
• 金额: $ 168.53万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8933803
• 关键词: Adrenal Glands; Alzheimer' s Disease; Amnesia; Animals; Attenuated; Behavioral; Biochemical; Biological; Brain; Calcium; Cell Nucleus; Cell membrane; Cell physiology; Cells; Cocaine; Disease; Endoplasmic Reticulum; Face; Foundations; Goals; Heart; Integral Membrane Protein; Kv1.2 potassium channel; Laboratories; Ligands; Liver; Lung; Malignant Neoplasms; Membrane; Mental Depression; Methamphetamine; Mitochondria; Molecular; Molecular Chaperones; Molecular Mechanisms of Action; National Institute of Drug Abuse; Neurons; Organ; Organelles; Organism; Pain; Pancrease; Parkinsonian Disorders; Peripheral; Personal Satisfaction; Play; Property; Protein Biosynthesis; Proteins; Psychostimulant dependence; Role; Signal Transduction; Spleen; Stroke; craving; endoplasmic reticulum stress; human disease; lipid metabolism; novel therapeutics; preclinical study; receptor; response; sensor; sigma receptors; sigma-1 receptor

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 (1) the Sig-1R can translocate to the plasma membrane to interact with potassium channel Kv1.2 to attenuate the intrinsic excitability of neurons that in turn enhances animal's behavioral responses to cocaine; (2) the Sig-1R chaperones the ER stress sensor IRE1 at the ER-mitochondrion interface and enhances the mitochondrion-ER-nucleus signaling for cellular survival; and (3) the ER-mitochondrion interface can also provide proper Ca2+ signaling from ER into mitochondria by utilizing the antiapoptotic protein BclxL to activate IP3 receptors at the interface.

自从我在NIDA IRP的实验室于1982年发现sigma-1受体（Sig-1 R）以来，许多临床前研究表明，Sig-1 R和相关配体与中风，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。我们发现Sig-1 Rs位于细胞内一个叫做内质网（ER）的细胞器中，内质网负责细胞内大多数蛋白质的合成。更具体地说，Sig-1 R定位于ER膜上的特定亚结构域，该亚结构域直接面对并接触另一种为细胞产生能量的细胞内细胞器，称为胞内因子。 因此，Sig-1 R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-1 R调节ER和Escherichia coli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-1 Rs是通过将蛋白质维持在适当的三结构域构型来调节蛋白质功能的分子伴侣，因此我们正在研究除了我们迄今发现的IP 3受体之外，哪些蛋白质可能被Sig-1 Rs伴侣化。通过这样做，我们可能会更好地了解这种分子伴侣Sig-1 R如何在许多疾病中发挥作用。在本财政年度我们发现：（1）Sig-1 R可转位至质膜，与钾通道Kv1.2相互作用，从而减弱神经元的内在兴奋性，进而增强动物对可卡因的行为反应;（2）Sig-1 R在ER-内质网界面上陪伴ER应激传感器IRE 1，并增强内质网-内质网-核信号传导以维持细胞存活;（3）ER-线粒体界面也可以通过抗凋亡蛋白BclxL激活界面上的IP 3受体，提供适当的Ca ~（2+）信号从ER进入线粒体。