METABOLISM AND FUNCTION OF CYCLIC NUCLEOTIDES

环核苷酸磷酸二酯酶(PDE)的作用是 催化和调节cAMP和cGMP的水解性 因此，这些核苷酸第二信使的功能。它 目前已知存在几种不同的PDE基因家族 在所有物种中。在某些情况下，S扮演的特定角色 不同的PDE同工酶是已知的。然而，在大多数组织中， 个别PDE的角色(S)尚未确定。这个 最近发现，在许多细胞中，环核苷酸水平 《快速振荡》强调了PDE对于 不仅调制环核苷酸信号的幅度 还有它的持续时间。扮演某一特定角色的好榜样 PDE对环核苷酸快速变化的调控作用 发生在光感受器外部节段。在这里，监管 光感受器PDE活性控制cGMP对 光线强度的变化。CGMP的这些变化依次 调节cGMP门控阳离子通道的活性 感光细胞外节膜。我们在这方面建议 应用程序，其他PDE在 嗅觉信号转导的调制以及可能在其他 必须对变化做出快速反应的生理过程。 这篇文章描述了三种常见的实验类型 申请。第一个建议是彻底描述一个新的 我们最近发现的依赖于CaM的PDE家族 在嗅觉神经元中高度表达。第二个建议是 确定几个不同的PDE系列是否以及如何，包括 这个新的基因，都参与了嗅觉信号转导。这个 Three建议继续寻找新的PDE同工酶 在嗅觉神经元和其他组织中都存在变异。 预计拟议的研究将增加我们的 对嗅觉调节机制的认识 转导。因为，PDE家族的一些成员也是 在其他组织中表达，包括 大脑、睾丸和心脏，我们预计会有很多 了解该同工酶家族在嗅觉中的作用 神经元也将适用于我们对 这些其他组织的生理学。最后，因为不同的PDE 同工酶在不同的细胞中表达，目前有 同工酶在药理上的应用 作为治疗剂的选择性PDE抑制剂。这是意料之中的 本研究中提出的表达系统的发展 应用程序还将极大地帮助开发这些 探员们。

Cyclic nucleotide phosphodiesterases (PDEs) serve the purpose of catalyzing and regulating the hydrolysis cAMP and cGMP and thereby the functions of these nucleotide second messengers. It is now known that several different gene families of PDEs exist in all species. In some cases the specific role(s) played by different PDE isozymes are known. However, in most tissues the role(s) for individual PDEs have not yet been determined. The recent realization that in many cells cyclic nucleotide levels oscillate rapidly has emphasized the importance of the PDEs for modulating not only the amplitude of a cyclic nucleotide signal but also its duration. A good example for a specific role played by a PDE in the modulation of rapid changes in cyclic nucleotides occurs in the photoreceptor outer segments. Here regulation of photoreceptor PDE activity controls the response of cGMP to changes in light intensity. These changes in cGMP in turn modulate the activity of a cGMP-gated cation channel in the photoreceptor outer segment membranes. We suggest in this application that other PDEs perform a similar function in the modulation of olfactory signal transduction and probably in other physiological processes that must rapidly respond to change. Three general types of experiments are described in this application. The first proposes to thoroughly characterize a new family of CaM-dependent PDEs that we have recently discovered to be highly expressed in olfactory neurons. The second proposes to determine if and how several different PDE families, including this new one, are involved in olfactory signal transduction. The third proposes to continue the search for new PDE isozyme variants both in olfactory neurons and other tissues. It is expected that the proposed studies will add to our knowledge about the mechanisms of regulation of olfactory sensory transduction. Since, some members of the PDE family are also expressed in other tissues, including specific regions of the brain, testis, and heart, it is expected that much of what we learn about the function of this family of isozymes in olfactory neurons will also be applicable to our understanding of the physiology of these other tissues. Finally, because different PDE isozymes are expressed in different cells, there is currently great interest in the pharmacological application of isozyme selective PDE inhibitors as therapeutic agents. It is expected that the development of the expression systems proposed in this application will also greatly aid in the development of these agents.