FUNCTION OF NACH RECEPTORS IN C ELEGANS MOTOR NEURONS

神经元烟碱乙酰胆碱受体（nAChR）是一个表达丰富且分子多样的阳离子通道蛋白家族，其介导脑中的关键生理功能。学习、记忆和伤害感受与胆碱能活动有关。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）与胆碱能信号的缺陷有关。神经元nAChR亚基以多种组合相关联以产生五聚体受体，其在结合到神经递质乙酰胆碱后促进阳离子转运。虽然至少有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.优雅该项目的目标是确定这些nAChR蛋白在C.运动神经元至少五种不同的nAChR亚基基因（“MnAChR”）在C.运动神经元虽然在脊椎动物脊髓中也检测到nAChR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。明确的神经解剖和相对简单的C。elegans运动神经元电路将有助于我们检测运动神经元特异性表达和确定这些nAChR亚单位的细胞内定位。此外，我们还将利用C. elegans检测nAChR基因之间的功能相互作用，并进行遗传筛选，可以揭示这些信号通路的新组件。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，也介导人类大脑中的胆碱能信号。

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.