Analysis of tyraminergic signaling in Caenorhabditis elegans

描述（由申请人提供）：微量胺酪胺与多种人类神经系统疾病有关，包括抑郁症、偏头痛、精神分裂症和药物滥用。尽管人们对酪胺在中枢神经系统中的作用知之甚少，但最近对可被酪胺激活的哺乳动物G蛋白偶联受体的表征引起了人们对酪胺在人类生理学和疾病中的作用的新兴趣。该提案的长期目标是了解酪胺如何在分子、细胞和神经回路水平上发挥作用来控制行为。为此，将在线虫秀丽隐杆线虫的简单神经系统中分析酪胺能信号传导机制。我们的分析表明，线虫具有独特的酪胺能细胞，并且酪胺调节多种行为。该项目将结合药理学、遗传学和电生理学技术来了解酪胺的功能。 SHO-1（我们实验室分离的一种新型离子型酪胺受体）的药理学和表达谱的分析将有助于深入了解它如何调节不同神经回路的输出。对 sho-1 突变体以及 G 蛋白偶联酪胺受体 ser-2 和 tyra-2 突变体的行为分析应该揭示离子型和代谢型途径如何协调控制酪胺依赖性行为。对神经肌肉接头处酪胺突触传递的电生理学分析应确定酪胺如何影响突触后特性。最后，将进行公正的遗传筛选，以寻找对外源酪胺具有抗性的突变体。此类突变体的表征应鉴定新的信号传导成分并阐明酪胺受体下游的信号传导事件。这些实验将为酪胺如何改变神经回路的输出和控制动物行为提供多层次的视角。鉴于酪胺与神经系统疾病的联系，这些研究最终将加速我们对酪胺在人类生理和疾病中功能的理解。公共健康相关性：尽管大脑化学物质酪胺与多种神经系统疾病有关，包括毒瘾、抑郁症、注意力过度缺乏症、帕金森病、精神分裂症和头痛，但人们对其功能知之甚少。由于我们对人类疾病的大部分了解都来自对诸如线虫、秀丽隐杆线虫等简单生物体的研究，因此我们建议研究酪胺如何在分子和细胞水平上控制这种动物的行为。我们的研究将更好地了解酪胺在大脑中的功能作用，最终目标是治疗和预防人类神经系统疾病。

DESCRIPTION (provided by applicant): The trace amine, tyramine, has been implicated in a variety of human neurological disorders, including depression, migraine, schizophrenia and drug abuse. Although the role of tyramine in the CNS is poorly understood, the recent characterization of mammalian G-protein coupled receptors that can be activated by tyramine has aroused new interest in the role of tyramine in human physiology and disease. The long-term objective of this proposal is to understand how tyramine operates at the molecular, cellular, and neural circuit level to control behaviors. To this end, mechanisms of tyraminergic signaling will be analyzed in the simple nervous system of the nematode Caenorhabditis elegans. Our analysis has established that C. elegans has distinct tyraminergic cells and that tyramine regulates several behaviors. This project will use a combination of pharmacological, genetic, and electrophysiological techniques to understand tyramine function. Analysis of the pharmacological and expression profile of SHO-1, a novel ionotropic tyramine receptor isolated in our laboratory, will provide insight into how it modulates the output of distinct neural circuits. Behavioral analysis of sho-1 mutants, together with that of mutants for the G-protein coupled tyramine receptors ser-2 and tyra-2, should reveal how ionotropic and metabotropic pathways coordinately control tyramine dependent behaviors. Electrophysiological analysis of tyramine synaptic transmission at the neuromuscular junction should establish how tyramine affects postsynaptic properties. Lastly, an unbiased genetic screen will be conducted to search for mutants resistant to exogenous tyramine. Characterization of such mutants should identify novel signaling components and elucidate the signaling events downstream of tyramine receptors. These experiments will provide a multi-level perspective on how tyramine changes the output of neural circuits and controls animal behavior. Given tyramine's link with neurological disorders, these studies should ultimately accelerate our understanding of tyramine function in human physiology and disease. PUBLIC HEALTH RELEVANCE: Although the brain chemical, tyramine, is linked to a large variety of neurological disorders, including drug addiction, depression, attention hyper deficit disorders, Parkinson's disease, schizophrenia and headaches, little is known about its function. Since much of our understanding in human disease has come from studies of simple organisms like the round worm, Caenorhabditis elegans, we propose to study how tyramine controls behavior of this animal at the molecular and cellular level. Our studies will provide a better understanding of the functional role of tyramine in the brain, with the ultimate goal of treatment and prevention of human neurological disorders.