ANATOXIN AND ITS ANALOGS AS NEUROTRANSMITTERS

描述：(改编自申请人的摘要)本提案 解决有关电生理学和分子生物学的基本问题 新近发现的和本质上的药理机制 烟碱型乙酰胆碱的未知异质性种群 受体(AChRs)位于大脑的不同区域。精准的 对这种难以捉摸的受体的功能特性的了解是 对了解大脑生理学的重要意义 在正常情况下和在疾病状态下。新型神经毒素(+) 类毒素-a(ANTX)及其合成类似物，包括(-)对映体 已经被证明是揭示激动症的结构要求的关键 肌肉AChR。此外，凭借其效力和特异性， (+)Antx使中枢AChR电流的记录成为可能 系统(CNS)，并揭示AChRs的高度异质性， 无论是在同一细胞内还是在不同细胞类型之间。因此，新的 这个项目的长期目标是研究基本的功能 和AChR在不同阶段的药理作用 在长期接触所选药物的情况下，儿童的身体发育也会受到影响。在……里面 除ACh和Antx类似物外，其他选定的弱激动剂 类似的特异性将用于研究中枢神经系统的AChR反应。 已记录的外围设备的非竞争性对手 ACHR现在将在中枢神经系统进行研究，包括一系列新的吖啶类化合物 阿拉芬类似物，其功能是作为敏感的“尺子”来定义 AChR上的拮抗部位。这些选择性毒素的影响将 也在N-甲基-D-天冬氨酸受体上进行研究，因为 已观察到的结构和功能同源性的处理 外周和中枢AChR。这些研究对于 对同源配体门控通道相互关系的认识 以及相关的疾病状态，如阿尔茨海默氏症。建议数 实验将利用各种电生理技术， 包括在此开发的一种新的快速药物灌流和撤药系统 实验室，加上配基结合，荧光标记，和 受体的动力学研究和急性期的形态研究 分离和组织培养神经细胞以揭示基本的 这些不同形式的乙酰胆碱受体功能的潜在机制。

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.