Pharmacology and Regulation of Nicotinic Receptor Subtypes

我们的目标是评估不同的异聚体神经元烟碱的药理学和调节， 哺乳动物中枢神经系统（CNS）中的胆碱能受体（nAChR）亚型。这些受体是 广泛分布于中枢神经系统，在中枢神经系统中，它们调节重要神经元中几种神经递质的释放。 途径。因此，它们影响广泛的功能，并且它们已明确与尼古丁有关。 成瘾此外，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。 所述疾病包括帕金森病、阿尔茨海默病、图雷特综合征和神经性疼痛。 尼古丁受体对自主神经系统的正常功能也至关重要，因此它们 几乎影响身体的所有器官系统。这些受体是由11个 亚基代表两个类别，α和β。受体的亚基组成决定了它的亚型， 决定了它的药理学和生物物理学特性，这些特性在不同的药物中有细微的变化，或者不那么细微。 特定的亚型两种nAChR亚型似乎形成了其他几种异聚体的主要模板。 在中枢神经系统和自主神经系统中发现的受体。基于α 4 β 2亚型的受体在中枢神经系统的大部分区域中占主导地位;而α 3 β 4亚型提供了主要的自主神经节模板。本研究的具体目的是：1）定量脑区的α 4 β 2 α 5亚型，并确定α 5亚基对尼古丁调节这些受体的影响; 2）研究含α 6亚基的nAChR的亚基组成、药理学和调节;和3）使用一种强有力的新方法，表达由融合成单一确定受体的所有五个亚基组成的多联体受体，以确定已知亚基组成、化学计量，和亚单位的顺序。本提案中描述的研究将有助于更好地了解这些不同受体亚型之间药理学和调节的重要差异，并帮助我们了解尼古丁如何调节CNS nAChR。

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.