ANATOXIN AND ITS ANALOGS AS NEUROTRANSMITTERS

描述：（改编自申请人摘要）本提案 涉及电生理学和分子生物学的基本问题 最近发现的药理学机制， 烟碱乙酰胆碱的非特征性异质群体 受体（AChR）位于大脑的各个区域。 的精确 这种难以捉摸的受体的功能特性的知识， 对理解大脑生理学的重要意义 在正常情况下和疾病状态下。 新型神经毒素（+） 类毒素-a（AnTX）及其合成类似物，包括（-）对映体 已被证明对于揭示激动作用的结构要求至关重要， 肌肉乙酰胆碱受体 此外，由于其效力和特异性， （+）AnTX能够记录中枢神经系统中的AChR电流 系统（CNS），并揭示了AChRs的高度异质性， 在同一细胞内和不同细胞类型之间。 因此，新 该项目的长期目标是研究基本功能 和药理学性质的AChR在不同阶段的 发展和慢性暴露于选定的药物的条件下。 在 除了ACh和AnTX类似物之外，其它选择的弱激动剂， 类似的特异性将用于研究CNS中的AChR应答。 已记录的外周血中的非竞争性拮抗剂 AChR现在将在中枢神经系统中进行研究，包括一系列新的吖啶 作为敏感的“统治者”来定义 AChR上的拮抗剂位点。 这些选择性毒素的作用 也可以在N-甲基-D-天冬氨酸受体进行研究，因为 大量的结构和功能同源性，已被观察到与 外周和中枢AChR。 这些研究对于 了解同源配体门控通道的相互关系 和相关疾病状态，如阿尔茨海默氏痴呆症。 拟议 实验将利用各种电生理学技术， 其中包括一种新的快速药物灌注和撤回系统， 实验室，配体结合，荧光标记， 受体的动力学研究，以及急性 分离和组织培养的神经细胞，以揭示基本的 这些不同形式的乙酰胆碱受体的功能机制。

DESCRIPTION: (Adapted from the applicant's abstract) This proposal addresses basic questions concerning the electrophysiological and molecular pharmacological mechanisms of the recently identified and essentially uncharacterized heterogeneous populations of nicotinic acetylcholine receptors (AChRs) located in various regions of the brain. The precise knowledge of the functional properties of such an elusive receptor is of major significance for the understanding of the physiology of the brain under normal conditions and in disease states. The novel neurotoxin (+) anatoxin-a (AnTX) and its synthetic analogs including the (-) enantiomer have proven essential to uncover the structural requirements for agonism at the muscle AChR. Furthermore, by virtue of its potency and specificity, (+)AnTX has enabled the recording of AChR currents in the central nervous system (CNS) and to reveal a great degree of heterogeneity of the AChRs, both within the same cell and among different cell types. Thus, the new long-term goal of this project is to investigate the fundamental functional and pharmacological properties of the AChR at different stages of development and under conditions of chronic exposure to selected drugs. In addition to ACh and the AnTX analogs, other selected weak agonists with similar specificity will be used to investigate AChR responses in the CNS. The noncompetitive antagonists that have been documented for the peripheral AChR will now be studied in the CNS, including a novel series of acridine araphane analogs which function as sensitive "rulers" to define the antagonist sites on the AChR. The effects of these selective toxins will also be studied at the N-methyl-D-aspartate receptor because of the great deal of structural and functional homology that has been observed with peripheral and central AChR. These studies are essential for the understanding of the interrelationships of homologous ligand-gated channels and related disease states such as Alzheimer's dementia. The proposed experiments will utilize a variety of electrophysiological techniques, including a new fast drug perfusion and withdrawal system developed in this laboratory, coupled with ligand binding, fluorescence labelling, and kinetic studies of receptors, and morphological studies of acutely dissociated and tissue cultured neuronal cells to reveal the basic mechanisms underlying the function of these different forms of AChR.