权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Sigma Receptor Structure /Function /K+ Channel Modulation

Sigma受体结构/功能/K通道调制

基本信息

批准号：
7173795
负责人：
Arnold Eino Ruoho
金额：
$ 30.82万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-01-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7173795
关键词：
Affinity Affinity Labels Agonist Amino Acids Antipsychotic Agents Area Behavioral Binding Binding Sites Biological Assay Cell membrane Chimeric Proteins Class Classification Cocaine Competitive Binding Electrophysiology (science)Epitopes Exhibits Generations Haloperidol Human Immunoprecipitation Immunosuppressive Agents Ion Channel Laboratories Lead Ligand Binding Ligands Maps Mediating Methodology Molecular Biology Mus Mutagenesis N-terminal Neuraxis Numbers Opioid Receptor Organ Pentazocine Peptides Peripheral Pharmaceutical Preparations Photoaffinity Labels Potassium Channel Property Proteins Radioactive Recombinant Fusion Proteins Reporting Research Research Proposals Schizophrenia Structure T-Lymphocyte Therapeutic Uses Voltage-Gated Potassium Channel Work Yeasts affinity labeling fenpropimorph genetic linkage mutant novel receptor receptor binding receptor structure function research study response sigma receptors voltage yeast two hybrid system

项目摘要

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“非阿片类”受体。σ受体的功能尚不清楚，但据信其介导药物的免疫抑制剂、抗精神病药和神经保护作用，所述药物例如氟哌啶醇、二甲苯基胍（DTG）、喷他佐辛和可卡因。几个观察结果表明σ配体的潜在治疗用途。一些非典型的神经抑制剂（例如，氟哌啶醇）对σ受体具有高亲和力，这导致了产生一类新的抗精神病药物的可能性，所述抗精神病药物缺乏多巴胺能活性并且可以选择性地结合σ受体。据报道，sigma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。这些观察结果提高了sigma受体可能是治疗可卡因相关反应的靶点的可能性。强效免疫抑制剂SR 31747 A与σ受体结合，在小鼠和人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sigma配体的免疫抑制特性，并导致新一代免疫抑制剂。许多研究表明，σ受体配体调节质膜中的离子通道以调节兴奋性。靶通道是一般的电压门控K+通道，并且调制需要抑制由正电压阶跃引起的电流。这项研究的重点是表征sigma 1受体结合位点的结构和sigma 1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σ 1受体的配体结合位点;（3）测定σ 1受体与Kv1.4钾通道和其他蛋白质伴侣相互作用的性质。这些实验将通过光活化分子、电生理学、重组蛋白和融合蛋白的组合使用来进行。