Novel Neuronal nAChR-Targeted Peptides

描述(摘自申请人的摘要)： 烟碱型乙酰胆碱受体(NAChRs)调节多种神经递质的释放 中枢神经系统(CNS)的关键神经递质。药理作用 操纵这些受体的功能可能有益于 治疗各种影响精神健康的疾病，包括 精神分裂症，抽动症，注意缺陷多动障碍， 情绪障碍、阿尔茨海默氏症和慢性疼痛。 圆锥属肉食性海洋蜗牛的毒液是一种非同寻常的 丰富的化合物来源(CX-芋螺毒素)，可有效和选择性地靶向 特定的nAChR亚型。这项提案的目的是确定和 描述来自这些毒液的化合物的特征，区分不同的 神经元nAChRs的ACh结合亚单位接口。这一目标将是 通过使用基于受体的分析来跟踪活性物质的纯化 毒液化合物。编码椰螺毒素的基因也将被克隆，以分离出新的 毒素。通过任何一种方法鉴定的多肽都将是生化的 进行了表征和合成。然后，这些多肽将被充分表征 关于受体亚型特异性，并用于检查亚单位 介导神经递质释放的突触前nAChRs的组成 神经递质。 当前研究的一个主要方向是确定不同基因中的亚基 NAChRs功能通道亚型及其在健康中的作用 和疾病。针对nAChR亚型的选择性探针的可用性将 极大地促进了这些努力，并为发展 能够调节nAChR介导的特定功能的药物 神经系统。

DESCRIPTION(From applicant's abstract): Nicotinic acetyicholine receptors (nAChRs) modulate the release of a number of key neurotransmitters in the central nervous system (CNS). Pharmacological manipulation of the function of these receptors may be beneficial in the treatment of a variety of disorders that impact mental health including schizophrenia, Tourette's syndrome, attention deficit hyperactivity disorder, mood disorders, Alzheimer's disease and chronic pain. Venom from carnivorous marine snails of the genus Conus are an extraordinarily rich source of compounds (cx-conotoxins) that potently and selectively target specific nAChR subtypes. The aim of this proposal is to identify and characterize compounds from these venoms that discriminate among distinct ACh-binding subunit interfaces of neuronal nAChRs. This aim will be accomplished by using receptor-based assays to track the purification of active venom compounds. Genes encoding a-conotoxins also will be cloned to isolate new toxins. Peptides identified by either approach will be biochemically characterized and synthesized. These peptides will then be fully characterized with respect to receptor subtype specificity and used to examine the subunit composition of presynaptic nAChRs that mediate the release of neurotransmitters. A major thrust of current research is to identify the subunits in the different functional channel subtypes of nAChRs and to understand their roles in health and disease. The availability of selective probes for the nAChR subtypes will greatly facilitate these efforts and provide a platform for development of medications capable of modulating specific nAChR-mediated functions in the nervous system.