Biological/Biochemical Characterization: Sigma Receptors

生物学/生化表征：Sigma 受体

• 批准号: 7149281
• 负责人: Tsung-Ping Ping Su
• 金额: --
• 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/7149281
• 关键词: axon; biochemistry; brain morphology; cell differentiation; cell membrane; dendrites; endoplasmic reticulum; enzyme activity; lipid transport; membrane structure; mitogen activated protein kinase; molecular biology; neuropharmacology; oligodendroglia; opioid receptor; protein structure function

This project delineates biochemical and pharmacological properties of sigma-1 receptors (S-1R). S-1R are one-transmembrane proteins at the endoplasmic reticulum (ER) that bind neurosteroids, dextrobenzomorphans, and certain psychostimulants such as cocaine. The brain is highly enriched in lipids. However, the molecular biological roles of lipids in the brain have been largely unexplored. Although, in 1990s, several studies have demonstrated the roles of lipids in a variety of neuronal functions and certain neurological diseases, the involvement of lipids in drug dependence, if any, is almost totally unknown. Sigma-1 receptors possess a putative sterol-binding pocket and are predominantly expressed on the endoplasmic reticulum (ER) where most lipids and their precursors are synthesized. Sigma-1 receptors are involved in drug-seeking behaviors and in psychostimulant-induced behavioral sensitization. Recent studies demonstrated that sigma-1 receptors target the lipid-storing subcompartments of the ER and are colocalized with cholesterol and neutral lipids. Sigma-1 receptors form detergent-insoluble lipid microdomains (lipid rafts) on the ER subcompartments and can translocate on the ER when stimulated. Upregulation of sigma-1 receptors affect the levels of plasma membrane lipid rafts by changing the lipid components therein. The membrane reconstitution thus induced by sigma-1 receptors in turn affects functions of proteins residing in plasma membrane lipid rafts including tropic factor receptors and tyrosine kinases. Specifically, we found that sigma-1 receptors modulate MAP kinase activation induced by tropic factors, neuritegenesis and oligodendrocyte differentiation-all related to lipid raft reconstitution. Sigma-1 receptors may thus play a role in psychostimulant-induced long-lasting morphological changes in the brain via the capacity of sigma-1 receptors in regulating ER lipid transport and the resultant plasma membrane lipid raft reconstitution.

该项目描述了 sigma-1 受体 (S-1R) 的生化和药理学特性。 S-1R 是内质网 (ER) 上的单跨膜蛋白，可结合神经类固醇、右旋苯并吗啡烷和某些精神兴奋剂（如可卡因）。大脑富含脂质。然而，脂质在大脑中的分子生物学作用在很大程度上尚未被探索。尽管在 20 世纪 90 年代，一些研究已经证明了脂质在各种神经元功能和某些神经系统疾病中的作用，但脂质是否与药物依赖有关（如果有的话）几乎完全未知。 Sigma-1 受体具有假定的甾醇结合袋，主要在内质网 (ER) 上表达，大多数脂质及其前体都是在这里合成的。 Sigma-1 受体参与药物寻求行为和精神兴奋剂诱导的行为敏化。最近的研究表明，sigma-1 受体靶向内质网的脂质储存亚区室，并与胆固醇和中性脂质共定位。 Sigma-1 受体在 ER 亚区室上形成去污剂不溶性脂质微结构域（脂筏），并且在受到刺激时可以在 ER 上易位。 sigma-1 受体的上调通过改变质膜脂筏中的脂质成分来影响质膜脂筏的水平。由 sigma-1 受体诱导的膜重建反过来又影响质膜脂筏中蛋白质的功能，包括热带因子受体和酪氨酸激酶。具体来说，我们发现 sigma-1 受体调节由热带因子、神经突发生和少突胶质细胞分化诱导的 MAP 激酶激活，所有这些都与脂筏重建有关。因此，Sigma-1 受体可能通过 sigma-1 受体调节 ER 脂质转运和由此产生的质膜脂筏重建的能力，在精神兴奋剂诱导的大脑长期形态变化中发挥作用。