Pharmacology and Regulation of Nicotinic Receptor Subtypes

我们的目标是评估不同异构体神经元烟碱的药理学和调节作用。 哺乳动物中枢和自主神经系统的胆碱能受体(NAChR)亚型。这些 受体广泛分布在中枢神经系统，在那里它们调节几种神经递质的释放。 重要的神经通路。因此，它们影响了CMS的广泛功能，而且它们已经 显然与尼古丁成瘾有关。此外，这些受体被认为在 其他多种CMS疾病，包括帕金森氏病、阿尔茨海默病、多发性抽动症 和神经病理性疼痛。尼古丁受体对自主神经的正常功能也是至关重要的。 因此，它们几乎影响到人体的所有器官系统。这些受体是五聚体。 由11个子单元组成的结构，代表两个类别，a和ft。分子的亚基组成 受体定义了它的亚型，并决定了它的药理和生物物理特性，这些特性是不同的 在特定的子类型中，微妙地或不微妙地。两个nAChR亚型似乎构成了主要的 中枢神经系统和自主神经系统中发现的其他几种异构体受体的模板。 以A4/？2亚型为基础的受体在中枢神经系统的大部分区域占优势，而A3/？4亚型则以A3/？4亚型为主 提供了两个重要的自主神经节的主要模板：交感上颈神经节 和副交感神经节。本建议所述各项研究的具体目的如下：1) 对脑区A402A5亚型进行量化，并确定A5亚基对脑功能的影响。 尼古丁对这些受体的调节；2)识别、量化和表征几种不同的 NAChR亚型在颈上神经节和结状神经节中的分布 不同受体亚型被运输到这些神经节神经元的轴突终末；3)研究 含有a6亚基的nAChRs的亚基组成、药理和调节；以及4)使用 测定已知亚基混合异构体nAChRs性质的新方法 组成、化学计量和亚基顺序。这项提案中描述的研究将导致更好的 了解这些不同受体在药理和调节方面的重要差异 并帮助我们理解尼古丁是如何上调CNS nAChRs的。

Our objectives are to assess the pharmacology and regulation of the diverse heteromeric neuronal nicotinic cholinergic receptor (nAChR) subtypes in the mammalian CNS and autonomic nervous system. These receptors are widely distributed in the CNS, where they modulate release of several neurotransmitters in important neuronal pathways. Thus, they influence a wide range of CMS functions, and they have been clearly implicated in nicotine addiction. In addition, these receptors are thought to play an important role in a wide range of other CMS disorders including Parkinson's disease, Alzheimer's disease, Tourette's syndrome and neuropathic pain. Nicotinic receptors are also crucial for normal functioning of the autonomic nervous system, and thus they influence virtually all organ systems in the body. These receptors are pentameric structures assembled from 11 subunits representing 2 classes, a and ft. The subunit composition of a receptor defines its subtype and determines its pharmacological and biophysical properties, which vary subtly or not so subtly, among the particular subtypes. Two nAChR subtypes seem to form the main templates for several other heteromeric receptors found in the CNS and autonomic nervous systems. Receptors based on the a4/?2 subtype predominate in most areas of the CNS; whereas, the a3/?4 subtype provides the main template for two important autonomic ganglia: the sympathetic superior cervical ganglia and the parasympathetic nodose ganglia. The specific aims of the studies described in this proposal are: 1) To quantify the a402a5 subtype in brain areas and determine the influence of the a5 subunit on the regulation of these receptors by nicotine; 2) To identify, quantify and characterize the several different nAChR subtypes in the superior cervical ganglia and the nodose ganglia and to determine which of the different receptor subtypes are transported to the axon terminals of these ganglion neurons; 3) To study the subunit composition, pharmacology and regulation of nAChRs containing a6 subunits; and 4) To use a powerful new method to determine the properties of mixed heteromeric nAChRs of known subunit composition, stoichiometry, and subunit order. The studies described in this proposal will lead to a better understanding of important differences in the pharmacology and regulation among these different receptor subtypes and help us to understand how nicotine up-regulates CNS nAChRs.