FUNCTIONAL PROPERTIES OF NEURONAL NICOTINIC RECEPTORS

烟碱型乙酰胆碱受体的一个主要区别是 中枢神经系统(CNS)和特征更好的骨骼 肌肉烟碱受体是中枢神经系统的显著异质性 感受器。大量克隆的中枢神经系统尼古丁受体亚单位为 这种异质性的基础，这已在药理学中得到证实 内源性受体的研究。异源表达一直很有用 用于识别潜在的受体亚型，但现在很明显 在卵母细胞中表达的神经元受体的特性并不总是 等同于天然受体的基因组成 天然中枢尼古丁受体的结构比以前更复杂 想着。目前，内源性中枢尼古丁受体的研究很少。 理解，由于缺乏针对这些特征的研究 受体在原位。该项目的目标是使用 电生理、药理和生化技术 定义原生突触前和突触后中枢神经系统的特性 尼古丁受体，并研究尼古丁受体的后果 中枢神经系统在细胞水平上的激活。 释放研究和解剖学研究的证据表明， 中枢神经系统尼古丁受体的很大一部分被定位 在突触前，它们增加神经递质的释放。 电生理证据证实尼古丁受体增强 突触前递质释放是在过去的资助期内获得的。 雏鸡脑片全细胞膜片钳电生理学 用于检测γ-氨基丁酸对烟碱的增强作用 (GABA)释放，通过外侧的单独机制发生。 螺旋状核(SPL)和腹侧膝状核(GLV)。 问题包括：尼古丁增强递质释放吗？ 依赖于通过突触前烟碱受体的钙离子流动？是 不同亚型的受体参与其中吗？哪些神经递质 受尼古丁受体调节吗？ 中枢神经系统中的突触后尼古丁受体也将被表征 应用细胞贴片研究单一烟碱的性质 感受器通道以及全细胞记录。神经元表达 不同亚型的尼古丁受体将在脑片上贴片 在急性解离之后，尼古丁的异质性 受体的评估将基于单通道属性和 药理学标准。突触前和突触前的发展 将SPL中的突触后尼古丁受体与 核团的功能性神经支配。受体可能的变化 发育过程中的亚型，已知在两个骨骼中都存在 肌肉和自主神经节，将进行评估。体内的烟碱受体 中枢神经系统在包括阿尔茨海默氏症在内的许多人类疾病中都会发生变化 和帕金森氏症。吸烟使人上瘾的特征， 一个主要的健康问题，是由于尼古丁在中枢神经系统的作用 尼古丁受体。了解这些受体如何调节 因此，大脑中的神经传递对人类健康非常重要。

A major distinction between nicotinic acetylcholine receptors located in the central nervous system (CNS) and the better characterized skeletal muscle nicotinic receptors is the remarkable heterogeneity of CNS receptors. Numerous cloned CNS nicotinic receptor subunits provide the basis for this heterogeneity, which has been confirmed in pharmacological studies of endogenous receptors. Heterologous expression has been useful for identifying potential receptor subtypes, but it is now apparent that the properties of neuronal receptors expressed in oocytes are not always equivalent to those of native receptors, and that the genetic composition of native CNS nicotinic receptors is more complex than previously thought. At present, endogenous CNS nicotinic receptors are poorly understood, due to a paucity of studies directed at characterizing these receptors in situ. The goal of this project is to use electrophysiological, pharmacological and biochemical techniques to define the properties of native presynaptic and postsynaptic CNS nicotinic receptors and to examine the consequences of nicotinic receptor activation in the CNS at the cellular level. Evidence from release studies and anatomical work indicates that a significant portion of CNS nicotinic receptors are located presynaptically, where they increase the release of neurotransmitters. Electrophysiological evidence confirming that nicotinic receptors enhance presynaptic transmitter release was obtained in the past funding period. Whole-cell patch-clamp electrophysiology in chick brain slices will be used to examine the nicotinic enhancement of gamma-amino-butyric acid (GABA) release, which occurs via separate mechanisms in the lateral spiriform nucleus (SPL) and the ventral lateral geniculate nucleus (GLV). Questions include: does nicotinic enhancement of transmitter release depend on Ca2+ flux through presynaptic nicotinic receptors? Are different subtypes of receptors involved? Which neurotransmitters are modulated by nicotinic receptors? Postsynaptic nicotinic receptors in the CNS will also be characterized using cell-attached patches to study the properties of single nicotinic receptor channels as well as whole-cell recordings. Neurons expressing different subtypes of nicotinic receptors will be patched in brain slices and following acute dissociation, and the heterogeneity of nicotinic receptors will be evaluated on the basis of single channel properties and pharmacological criteria. The development of presynaptic and postsynaptic nicotinic receptors in the SPL will be compared to that of functional innervation of the nucleus. Possible changes in receptor subtypes during development, which are known to occur in both skeletal muscle and autonomic ganglia, will be evaluated. Nicotinic receptors in the CNS are altered in a number of human diseases, including Alzheimer's and Parkinson's Disease. The addictive features of cigarette smoking, a major health concern, are due to the actions of nicotine at CNS nicotinic receptors. Understanding how these receptors regulate neurotransmission in the brain is thus important for human health.