Regulation and Function of Cyclic GMP in the CNS

描述（由申请人提供）： 几乎所有的细胞功能都受到各种不同的 细胞内信使该建议侧重于监管和功能 环鸟苷酸（cGMP）。其综合平衡和 分解调节细胞内cGMP的水平。cGMP的合成是 由鸟苷酸环化酶控制，直到最近， 鸟苷酸环化酶的种类主要有受体型和可溶性鸟苷酸环化酶。 受体鸟苷酸环化酶是一种膜内蛋白，受 细胞外肽激素或细胞内钙结合 proteins.这类鸟苷酸环化酶调节细胞中的cGMP水平。 肾脏和视网膜的光感受器中。可溶性鸟苷酸环化酶是 位于细胞质中，并且经典地由气体调节。 信使一氧化氮它们在调节血液方面特别重要 压力通过血管平滑肌张力。cGMP重要性的一个例子 对人类健康和疾病的影响表现在药物的广泛使用， 西地那非（伟哥），通过抑制一种酶， 通常分解cGMP。 我的实验室用昆虫，天蛾作为模式生物， 鸟苷酸环化酶的新类型。第一个与受体鸟苷酸有关 环化酶，但不是一个完整的膜蛋白。二是与 可溶性鸟苷酸环化酶，但对一氧化氮不敏感。我们有证据 这表明，这种一氧化氮不敏感可溶性鸟苷酸环化酶介导 一种调节特定行为程序的神经肽的作用， Manduca和另一种昆虫果蝇的相关生理变化 黑腹菌本提案的主要重点是检验这一假设 直接结合使用细胞和分子方法在曼杜卡与 果蝇的遗传学方法。此外，我们将使用分子和 生物化学技术，以确定参与的生化级联反应， 这种新型鸟苷酸环化酶的激活。 这些新的鸟苷酸环化酶类别的成员也存在于另一个 模式生物秀丽隐杆线虫。大多数信号转导级联是 在进化上高度保守，这些例子很可能 鸟苷酸环化酶将在哺乳动物中鉴定。更详细地了解 调节不同组织中cGMP水平的多种机制 毫无疑问，这将对广泛的细胞生理学基础产生重大影响， 各种系统。

DESCRIPTION (provided by applicant): Almost all cellular functions are modulated by a variety of different intracellular messengers. This proposal focuses on the regulation and function of one of these messengers, cyclic GMP (cGMP). The balance of its synthesis and breakdown regulates the level of cGMP within a cell. The synthesis of cGMP is controlled by the enzyme guanylyl cyclase and until recently two main classes of guanylyl cyclase were known, receptor and soluble guanylyl cyclases. Receptor guanylyl cyclases are integral membrane proteins that are regulated by either extracellular peptide hormones or intracellular calcium-binding proteins. Guanylyl cyclases of this class regulate the cGMP levels in the kidney and in the photoreceptors of the retina. Soluble guanylyl cyclases are located in the cytoplasm and have classically been regulated by the gaseous messenger, nitric oxide. They are particularly important in regulating blood pressure via vascular smooth muscle tone. An example of the importance of cGMP in human health and disease is shown by the widespread use of the drug, sildenafil (Viagra) that elevates cGMP levels by inhibiting an enzyme that normally breaks down cGMP. Using an insect, Manduca sexta, as a model organism my lab has identified two novel classes of guanylyl cyclase. The first is related to receptor guanylyl cyclases but is not an integral membrane protein. The second is related to soluble guanylyl cyclases but is nitric oxide insensitive. We have evidence to suggest that this nitric oxide-insensitive soluble guanylyl cyclase mediates the action of a neuropeptide that regulates a specific behavioral program and associated physiological changes in Manduca and another insect, Drosophila melanogaster. The major focus of this proposal is to test this hypothesis directly combining the use of cellular and molecular approaches in Manduca with a genetic approach in Drosophila. In addition, we will use molecular and biochemical techniques to determine the biochemical cascade involved in the activation of this novel guanylyl cyclase. Members of these novel classes of guanylyl cyclase are also present in another model organism, Caenorhabditis elegans. Most signal transduction cascades are highly evolutionarily conserved and it is likely that examples of these guanylyl cyclases will be identified in mammals. A more detailed knowledge of the variety of mechanisms that regulate the levels of cGMP in different tissues will undoubtedly have a significant impact basic cellular physiology in a wide variety of systems.