FUNCTION OF NACH RECEPTORS IN C ELEGANS MOTOR NEURONS

神经型烟碱型乙酰胆碱受体(NAChRs)是一个表达丰富、分子多样性的阳离子通道蛋白家族，在大脑中发挥着重要的生理功能。学习、记忆和伤害性感觉与胆碱能活动有关。尼古丁成瘾依赖于nAChR功能，人类重要的疾病(癫痫、精神分裂症、阿尔茨海默氏症)都与胆碱能信号缺陷有关。神经元nAChR亚单位以各种组合的形式结合在一起，产生五聚体受体，在与神经递质乙酰胆碱结合时促进阳离子转运。尽管至少有15种不同类型的脊椎动物nAChR亚基尚未确定。最近在一种更小、更简单的生物--线虫--线虫的基因组中发现了至少40个不同的nAChR亚单位基因，这一预测得到了强调。这个项目的目标是确定这些nAChR蛋白的一个子集在线虫运动神经元中的生理和行为作用。线虫运动神经元中至少表达5种不同的nAChR亚单位基因(“MnAChRs”)。虽然在脊椎动物脊髓中也检测到nAChR的表达，但nAChRs在哺乳动物运动神经元功能中的作用尚不清楚。线虫运动神经元的明确神经解剖学和相对简单的电路将有助于我们检测运动神经元的特异性表达，并确定这些nAChR亚单位的细胞内定位。此外，我们将利用线虫强大的遗传学来检测nAChR基因之间的功能相互作用，并进行遗传筛选，以揭示这些信号通路的新组成部分。最终，我们的方法应该揭示出功能上重要的和进化上保守的蛋白质，这些蛋白质也介导了人脑中的胆碱能信号。

Neuronal Nicotinic Acetylcholine Receptors (nAChRs) are an abundantly expressed and molecularly diverse family of cation channel proteins that mediated key physiological functions in the brain. Learning, memory, and nociception have been linked to cholinergic activity. Nicotine addiction depends on nAChR function and important human diseases (epilepsy, schizophrenia, Alzheimer's) have been linked to defects in cholinergic signaling. Neuronal nAChR subunits associate in a variety of combinations to produce pentameric receptors that facilitate cation transport upon binding to the neurotransmitter acetylcholine. Although at least 15 different types of vertebrate nAChR subunits have yet to be identified. This prediction is underscored by the recent discovery of at least 40 distinct nAChR subunit genes in the genome of a much smaller and simpler organism, the nematode, C. elegans. The goal of this project is to define the physiological and behavioral roles of a subset of these nAChR proteins in C. elegans motor neurons. At least five different nAChR subunit genes ("MnAChRs") are expressed in C. elegans motor neurons. Although nAChR expression has also been detected in the vertebrate spinal cord, the roles of nAChRs in mammalian motor neuron function are largely unknown. The well-defined neuroanatomy and relative simplicity of the C. elegans motor neuron circuit will facilitate our effort to detect motor neuron-specific expression and to define the intracellular localization of these nAChR subunits. In addition, we will exploit the powerful genetics of C. elegans to detect functional interactions between the nAChR genes and to perform genetic screens that can reveal new components of these signaling pathways. Ultimately, our approach should reveal functionally important and evolutionarily conserved proteins that also mediate cholinergic signaling in the human brain.