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。 哺乳动物中枢神经系统的胆碱能受体(NAChR)亚型。这些受体是 广泛分布于中枢神经系统，在那里它们调节重要神经元中几种神经递质的释放 小路。因此，它们影响着广泛的功能，而且它们显然与尼古丁有关 上瘾。此外，这些受体被认为在广泛的其他中枢神经系统中发挥重要作用。 疾病包括帕金森氏症、阿尔茨海默病、抽动症和神经病理性疼痛。 尼古丁受体对自主神经系统的正常功能也是至关重要的，因此它们 几乎影响到身体的所有器官系统。这些受体是五聚体结构，由11个 代表两个类别的亚基，阿尔法和贝塔。受体的亚基组成定义了它的亚型和 确定其药理和生物物理特性，这些特性在 特定子类型。两种nAChR亚型似乎构成了其他几种异构体的主要模板 中枢神经系统和自主神经系统中发现的受体。以α4beta2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alpha3beta4亚型提供了主要的自主神经节模板。这项研究的具体目的是：1)量化脑区中的α4β2α5亚型，并确定α5亚基对尼古丁调节这些受体的影响；2)研究含有α6亚基的nAChRs的亚基组成、药理和调节；以及3)使用一种强大的新方法，即由所有五个亚基组成的串联受体的表达，以确定已知亚单位组成、化学计量和亚基顺序的混合异构体nAChRs的性质。这项建议中描述的研究将使我们更好地了解这些不同受体亚型之间在药理学和调控方面的重要差异，并帮助我们了解尼古丁如何调节中枢神经系统nAChRs。

Our objectives are to assess the pharmacology and regulation of the diverse heteromeric neuronal nicotinic cholinergic receptor (nAChR) subtypes in the mammalian central nervous system (CNS). 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 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 CNS 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, alpha and beta. 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 alpha4beta2 subtype predominate in most areas of the CNS; whereas, the alpha3beta4 subtype provides the main template autonomic ganglia. The specific aims of the studies described in this proposal are: 1) To quantify the alpha4beta2alpha5 subtype in brain areas and determine the influence of the alpha5 subunit on the regulation of these receptors by nicotine; 2) To study the subunit composition, pharmacology and regulation of nAChRs containing alpha6 subunits; and 3) To use a powerful new method, expression of concatameric receptors consisting of all five subunits fused into a single defined receptor, 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 regulates CNS nAChRs.