Biological/Biochemical Characterization: Sigma Receptors

该项目描述了sigma-1受体（S-1 R）的生物化学和药理学特性。S-1 R是位于内质网（ER）的单跨膜蛋白，可结合神经类固醇、苯并吗啡类和某些精神兴奋剂（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。虽然在20世纪90年代，一些研究已经证明了脂质在各种神经功能和某些神经系统疾病中的作用，但脂质在药物依赖中的参与（如果有的话）几乎完全未知。σ-1受体具有推定的甾醇结合口袋，并且主要在内质网（ER）上表达，大多数脂质及其前体在内质网（ER）中合成。σ-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ER的脂质储存亚室，并与胆固醇和中性脂质共定位。σ-1受体在ER亚区室上形成去污剂不溶性脂质微区（脂筏），并且当受到刺激时可以在ER上移位。σ-1受体的上调通过改变其中的脂质组分来影响质膜脂筏的水平。因此，由σ-1受体诱导的膜重构反过来影响存在于质膜脂筏中的蛋白质的功能，包括向性因子受体和酪氨酸激酶。具体来说，我们发现sigma-1受体调节MAP激酶激活诱导的热带因素，神经突和少突胶质细胞分化-所有相关的脂筏重建。因此，σ-1受体可能通过σ-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脑中持久的形态学变化中发挥作用。

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.