Regulation and Function of Cyclic GMP in the CNS

CNS 中环 GMP 的调节和功能

• 批准号: 6779704
• 负责人: DAVID B MORTON
• 金额: $ 30.2万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-18 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779704
• 关键词: Caenorhabditis elegans; Drosophilidae; Manduca; antisense nucleic acid; arthropod genetics; central nervous system; cyclic GMP; ecdysone; enzyme activity; enzyme induction /repression; guanylate cyclase; hormone regulation /control mechanism; in situ hybridization; neurogenetics; nitric oxide; northern blottings; phosphoproteins; protein kinase; receptor; recombinant proteins; site directed mutagenesis

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.

描述（由申请人提供）： 几乎所有细胞功能都由多种不同的不同 细胞内使者。该提案着重于调节和功能 在这些使者之一，Cyclic GMP（CGMP）。其综合和 分解调节单元内CGMP的水平。 CGMP的合成是 由酶Guanyll Cyclase控制，直到最近两个主要类 Guanylyl循环酶是已知的，受体和可溶性鸟叶酸环酶。 受体鸟叶烷环酶是整体膜蛋白，受到调节的调节 细胞外肽激素或细胞内钙结合 蛋白质。该类别的Guanylyl循环酶调节CGMP水平 肾脏和视网膜的光感受器。可溶性鸟叶循环是 位于细胞质中，经典地受到气态的调节 信使，一氧化氮。它们在调节血液方面特别重要 通过血管平滑肌张力的压力。 CGMP重要性的一个例子 在人类健康和疾病中，该药物的广泛使用显示 西地那非（伟哥）通过抑制一种酶来提高CGMP水平 通常会分解CGMP。 使用昆虫，Manduca Sexta作为模型生物，我的实验室已经确定了两个 新颖的Guanylyl循环酶。第一个与受体瓜尼相关 循环酶，但不是整体膜蛋白。第二个与 可溶性鸟叶循环酶，但是一氧化氮不敏感的。我们有证据 建议这种一氧化氮无敏感的可溶性鸟叶循环介导 调节特定行为计划的神经肽的作用和 相关的生理变化和另一种昆虫果蝇的昆虫变化 Melanogaster。该提案的主要重点是检验该假设 直接结合使用Manduca中的细胞和分子方法与 果蝇中的遗传方法。此外，我们将使用分子和 生化技术来确定与 激活这种新型的Guanylyl环化酶。 这些新颖类的成员也存在于另一个环境中 模型有机体，秀丽隐杆线虫。大多数信号转导级联是 高度进化保守，可能是这些例子 在哺乳动物中将发现鸟叶酸环酶。对 调节不同组织中CGMP水平的各种机制 毫无疑问，将在广泛的 多种系统。