Sigma Receptor Structure /Function/K+ Channel Modulation

描述(申请人提供)：Sigma受体是一种独特的“非阿片”受体，存在于哺乳动物的中枢神经系统和周围器官中。Sigma受体的功能尚不清楚，但它被认为介导了药物的免疫抑制、抗精神病药和神经保护作用，如氟哌啶醇、二苯基胍(DTG)、五氮唑卡因和可卡因。一些观察表明，西格玛配体具有潜在的治疗用途。一些非典型的抗精神病药物(如氟哌啶醇)对Sigma受体有很高的亲和力，这导致了创造一类新的抗精神病药物的可能性，这些药物没有多巴胺能活性，可以选择性地与Sigma受体结合。已有报道称，Sigma受体与精神分裂症之间存在遗传联系。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。强大的免疫抑制剂SR31747A与Sigma受体结合，在小鼠和人类T淋巴细胞上显示出免疫抑制特性和抗增殖活性。这些观察结果可能解释可卡因和其他西格玛配体的免疫抑制特性，并导致新一代免疫抑制剂的出现。大量研究表明，Sigma受体配体通过调节质膜上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，调制需要抑制正电压阶跃引发的电流。本研究的重点是确定Sigma1受体结合部位的结构以及Sigma1受体调节K+通道的方式。将研究三个领域：(1)新型高亲和力Sigma受体激动剂和拮抗剂光亲和标记的合成和表征；(2)Sigma1受体的配体结合位点(S)的定位；(3)Sigma1受体与Kv1.4钾通道和其他蛋白质伙伴相互作用的性质的确定。这些实验将通过结合使用可光激活分子、电生理学以及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.