FUNCTION OF NACH RECEPTORS IN C ELEGANS MOTOR NEURONS

神经元烟碱乙酰胆碱受体（nAChRs）是一个表达丰富且分子多样的阳离子通道蛋白家族，在大脑中介导关键生理功能。学习、记忆和伤害感受都与胆碱能活动有关。尼古丁成瘾依赖于nAChR功能，重要的人类疾病（癫痫、精神分裂症、阿尔茨海默氏症）与胆碱能信号缺陷有关。神经元nAChR亚基以多种组合方式结合产生五聚体受体，促进与神经递质乙酰胆碱结合后的阳离子运输。尽管至少有15种不同类型的脊椎动物nAChR亚基尚未被确定。最近在一种更小更简单的生物体——线虫（C. elegans）的基因组中发现了至少40个不同的nAChR亚基基因，这进一步证实了这一预测。该项目的目标是确定这些nAChR蛋白的一个子集在秀丽隐杆线虫运动神经元中的生理和行为作用。至少有五种不同的nAChR亚基基因（“MnAChRs”）在秀丽隐杆线虫的运动神经元中表达。尽管在脊椎动物脊髓中也检测到nAChR的表达，但nAChR在哺乳动物运动神经元功能中的作用在很大程度上是未知的。秀丽隐杆线虫运动神经元回路的明确神经解剖学和相对简单性将有助于我们检测运动神经元特异性表达和定义这些nAChR亚基的细胞内定位。此外，我们将利用秀丽隐杆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成分。最终，我们的方法应该揭示功能上重要的和进化上保守的蛋白质，这些蛋白质也介导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.