Sigma Receptor Structure /Function /K+ Channel Modulation

描述（由申请人提供）：Sigma受体是一种独特的“非阿片”受体，存在于哺乳动物中枢神经系统和外周器官中。sigma受体的功能尚不清楚，但据信它介导了氟哌啶醇、二聚胍（DTG）、戊唑嗪和可卡因等药物的免疫抑制、抗精神病和神经保护作用。一些观察结果表明sigma配体的潜在治疗用途。一些非典型的抗精神病药（如氟哌啶醇）对西格玛受体具有高亲和力，这导致了创造一类新的抗精神病药物的可能性，这些药物缺乏多巴胺能活性，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sigma配体可以阻断可卡因的行为和毒性功能，可卡因也可以作为具有合理亲和力的sigma配体。这些观察结果提出了sigma受体可能是治疗可卡因相关反应的靶点的可能性。有效的免疫抑制剂SR31747A与sigma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，受体配体通过调节质膜中的离子通道来调节兴奋性。目标通道是一般的电压门控K+通道，调制需要抑制由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。将重点研究三个领域：(1)新型高亲和力sigma受体激动剂和拮抗剂光亲和力标签的合成和表征；(2)定位sigma1受体的配体结合位点；(3)确定sigma1受体与kv1 .4钾离子通道和其他蛋白伙伴相互作用的性质。这些实验将通过结合使用光激活分子、电生理学、重组和融合蛋白来进行。

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.