Sigma Receptor Structure/Function/K+ Channel Modulation

Sigma受体结构/功能/K通道调制

• 批准号: 7005693
• 负责人: Arnold Eino Ruoho
• 金额: $ 31.75万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7005693
• 关键词: Xenopus oocyte; affinity labeling; binding sites; chimeric proteins; cocaine; drug design /synthesis /production; drug receptors; electrophysiology; fluorescence resonance energy transfer; haloperidol; immunoprecipitation; intermolecular interaction; iodination; membrane activity; microsomes; morpholine; pentazocine; potassium channel; protein structure function; receptor expression; recombinant proteins; site directed mutagenesis; yeast two hybrid system

DESCRIPTION (provided by applicant): Sigma receptors are unique "non-opioid" receptors that are found in the mammalian central nervous system and peripheral organs. The function of the sigma receptor is unknown, but it is believed to mediate the immunosuppressant, antipsychotic, and neuroprotective effects of drugs, such as haloperidol, ditolylguanidine (DTG), pentazocine, and cocaine. Several observations indicate potential therapeutic uses of sigma ligands. Some atypical neuroleptics (e.g., haloperidol) have high affinity for the sigma receptor, which has led to the possibility of creating a new class of antipsychotic drugs, which are devoid of dopaminergic activity and can bind selectively to the sigma receptor. A genetic linkage has been reported for the sigma receptor and schizophrenia. Selective sigma ligands can block the behavioral and toxic functions of cocaine, and cocaine can also serve as a sigma ligand with reasonable affinity. These observations raise the possibility that the sigma receptor may be a target for the treatment of cocaine-related responses. The potent immunosuppressant SR31747A, which binds to the sigma receptor, exhibits immunosuppressive properties and antiproliferative activity in mouse and human T lymphocytes. These observations may explain the immunosuppressant properties of cocaine and other sigma ligands and lead to a new generation of immunosuppressants. A number of studies have shown that sigma receptor ligands modulate ion channels in the plasma membrane to regulate excitability. Target channels are general voltage-gated K+ channels, and the modulation entails an inhibition of the current elicited by positive voltage steps. The focus of this research proposal is to characterize the structure of the sigma1 receptor binding site and the manner by which the sigma1 receptor modulates K+ channels. Three areas of focus will be investigated: (1) synthesis and characterization of novel high affinity sigma receptor agonist and antagonist photo affinity labels; (2) mapping the ligand binding site(s) of the sigma1 receptor; and (3) determination of the properties of the sigma1 receptor interaction with Kvl.4 potassium channels and other protein partners. These experiments will be performed through the combined use of photoactivatable molecules, electrophysiology, and recombinant and fusion proteins.

描述（由申请人提供）：Sigma受体是在哺乳动物中枢神经系统和外周器官中发现的独特的“非阿片类”受体。西格玛受体的功能尚不清楚，但据信它可以介导氟哌啶醇、二甲苯胍 (DTG)、喷他佐辛和可卡因等药物的免疫抑制剂、抗精神病和神经保护作用。一些观察表明西格玛配体的潜在治疗用途。一些非典型精神安定药（例如氟哌啶醇）对西格玛受体具有高亲和力，这使得创造一类新型抗精神病药物成为可能，该类药物缺乏多巴胺能活性，并且可以选择性地与西格玛受体结合。据报道，西格玛受体与精神分裂症存在遗传联系。选择性σ配体可以阻断可卡因的行为和毒性功能，并且可卡因也可以作为具有合理亲和力的σ配体。这些观察结果提出了西格玛受体可能成为治疗可卡因相关反应的靶标的可能性。强效免疫抑制剂 SR31747A 可与 sigma 受体结合，在小鼠和人类 T 淋巴细胞中表现出免疫抑制特性和抗增殖活性。这些观察结果可以解释可卡因和其他西格玛配体的免疫抑制剂特性，并导致新一代免疫抑制剂的诞生。许多研究表明，西格玛受体配体调节质膜中的离子通道以调节兴奋性。目标通道是一般电压门控 K+ 通道，调制需要抑制正电压阶跃引起的电流。本研究计划的重点是表征 sigma1 受体结合位点的结构以及 sigma1 受体调节 K+ 通道的方式。将研究三个重点领域：（1）新型高亲和力σ受体激动剂和拮抗剂光亲和标记的合成和表征； (2) 绘制 sigma1 受体的配体结合位点图； (3) 确定 sigma1 受体与 Kvl.4 钾通道和其他蛋白质伴侣相互作用的特性。这些实验将通过光激活分子、电生理学以及重组和融合蛋白的结合使用来进行。