Regulation and function of cGMP in the nervous system

这个项目的长期目标是了解神经元的特性是如何通过 氧浓度和环鸟苷酸(CGMP)的变化。细胞内信使环GMP(CGMP)， 是许多生理过程的中介体，包括血管张力、肾功能、神经可塑性、 心肌收缩和光感受器功能。细胞中cGMP的水平受 它的合成和降解的平衡，通过鸟苷酸环化酶(GCs)，和它的降解，通过磷酸二酯酶。这 该项目旨在增加我们对神经细胞中cGMP的调节和功能的了解。 系统，专注于一类新发现的非典型可溶性GC(SGC)。传统的SGC是 一氧化氮(NO)的主要靶标。NO对非典型SGCs的激活作用较差。以下是例子 广泛存在于哺乳动物和无脊椎动物中，如昆虫和线虫。几行 有证据有力地支持这一假设，即至少这些非典型sGC的一些例子是分子的。 氧气传感器。我们计划以果蝇黑腹果蝇为模型，研究其功能 和非典型SGCs的调节，并检验它们作为氧传感器提供 向生物体提供局部氧气浓度的信息。生化技术将直接用于 评估氧气与酶的相互作用，生理和行为分析将检查 表达这些sGC的感觉神经元的特性决定它们是否充当氧气 传感器和调节对低氧的行为反应。用果蝇作为模型的优势之一 系统是可以相对容易地进行遗传操作来修改表达的 SGC和各种外源基因产物。短期和长期的生理学 低氧对哺乳动物的影响是众所周知的，然而，分子氧传感器的性质 目前仍有些不清楚。我们的结果将为理解动物如何感知缺氧提供新的信息。 这项研究的结果将为了解cGMP途径提供新的见解和理解。这个 这种信号系统的多样性直到现在才被认识到，制药行业正在积极地 开发专门针对cGMP调控的新化合物。这些化合物有望解决 各种各样的健康障碍，包括心血管、泌尿和神经问题。伟哥和 其他治疗勃起功能障碍的药物可能只是治疗勃起功能障碍的冰山一角 靶向cGMP介导的过程的化合物。

The long-term goal of this project is to understand how the properties of neurons are modulated by changes in oxygen concentration and cyclic GMP (cGMP). The intracellular messenger, cyclic GMP (cGMP), is a mediator of many physiological processes including vascular tone, kidney function, neural plasticity, cardiac muscle contractility and photoreceptor function. The levels of cGMP in a cell are regulated by a balance of its synthesis, by guanylyl cyclases (GCs), and its degradation, by phosphodiesterases. This project is aimed at increasing our understanding of the regulation and function of cGMP in the nervous system, focusing on a newly identified class of atypical soluble GCs (sGCs). Conventional sGCs are the primary targets for nitric oxide (NO). The atypical sGCs are poorly activated by NO. Examples are widespread, occuring in mammals and invertebrates such as insects and nematodes. Several lines of evidence strongly support the hypothesis that at least some examples of these atypical sGCs are molecular oxygen sensors. We plan to use the fruit fly, Drosophila melanogaster as a model to investigate the function and regulation of atypical sGCs and to test the hypothesis that they act as oxygen sensors providing information to the organism of the local oxygen concentration. Biochemical techniques will be used to directly assess the interaction of oxygen with the enzymes and physiological and behavioral analysis will examine the properties of the sensory neurons that express these sGCs to determine whether they act as oxygen sensors and mediate behavioral responses to hypoxia. One of the strengths of using Drosophila as a model system is the relative ease with which genetic manipulations can be carried out to modify the expression of the sGCs and a variety of exogenous gene products. The short-term and long-term physiological consequences of hypoxia in mammals are well known, however, the nature of the molecular oxygen sensor is still somewhat unclear. Our results will provide new information to understand how animals sense hypoxia. The results from this study will provide new insights and understanding of the cGMP pathway. The diversity of this signaling system is only now being,appreciated and the pharmaceutical industry is active in developing new compounds that specifically target cGMP regulation. These compounds promise to address a wide variety of health disorders including cardiovascular, urinary and neurological problems. Viagra and other pharmacological treatments for erectile disfunction are probably just the tip of the iceberg for compounds that target cGMP mediated processes.