Neuromodulators and Signaling Cascades in Retina

视网膜中的神经调节剂和信号级联

• 批准号: 6838763
• 负责人: P Michael Iuvone
• 金额: $ 34.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6838763
• 关键词: adenosine; biological signal transduction; cyclic AMP; dark adaptation; dopamine; dopamine receptor; electroretinography; gene expression; gene targeting; genetically modified animals; laboratory mouse; light adaptations; neuropeptides; neuroregulation; neurotransmitters; posttranslational modifications; retina; retinal adaptation; somatostatin; visual photoreceptor

DESCRIPTION (provided by applicant): Photoreceptor cells are the primary sensory neurons of the visual system. In addition to being regulated by light, aspects of photoreceptor physiology are subject to control by neuromodulators, such as dopamine, adenosine, somatostatin, and nitric oxide. Much of the data supporting a role for these substances in photoreceptor cell function is pharmacological in nature, obtained from non-mammalian vertebrates, and much remains to be learned about the signaling mechanisms involved. Our preliminary data in mouse led to the hypothesis that dopamine, acting on dopamine D4 receptors, plays a major role in regulating cAMP metabolism in photoreceptor cells by Ca 2+ -dependent regulation of adenylyl cyclase and by regulating gene expression for components of the signaling cascade that links light exposure to inhibition of cAMP formation. Preliminary data also show that dopamine plays a major role in adaptive responses of mouse retina to changing illumination, possibly through a cAMP-dependent mechanism. The present goal is to test these hypotheses and to thereby elucidate the signaling mechanisms whereby dopamine produces it's effects on photoreceptor gene expression and retinal function during light- and dark-adaptation. Using mouse retina as an experimental model, we will test the following predictions of hypotheses: (1) Dopamine D4 receptors on photoreceptor cells regulate gene expression of one or more components of the signaling pathway that couples light-exposure to suppression of cAMP synthesis. (2) Dysfunctional cAMP regulation in photoreceptors of dopamine D4 receptor deficient mice alters photoreceptor gene expression profiles and posttranslational modification of key gene products, such as phosducin. (3) Dopamine and light decrease photoreceptor cAMP levels by reducing the activity of Ca 2+ / calmodutin-stimulated adenylyl cyclases. (4) Decreased expression of Ca 2+ / calmodulin-stimulated adenylyl cyclase(s) leads to the abnormalities of light and dark adaptation seen in dopamine D4 receptor deficient mice. The results of these experiments will significantly enhance our understanding of how dopamine and cAMP modulate photoreceptor function, especially light- and dark-adaptation.

描述（由申请人提供）：感光细胞是视觉系统的主要感觉神经元。除了受光调节外，光感受器生理的各个方面还可以受到神经调节剂的控制，例如多巴胺，腺苷，生长体抑素和一氧化氮。这些物质在光感受器细胞功能中的作用的许多数据本质上是药理学，是从非哺乳动物脊椎动物获得的，关于所涉及的信号传导机制还有很多尚待了解。我们在小鼠中的初步数据导致了以下假设：多巴胺作用于多巴胺D4受体，在调节光感受器细胞中的cAMP代谢中起着主要作用，通过Ca 2+依赖性调节腺苷酰基环化酶的调节，并通过调节信号壳体的基因表达来链接到扎营的组成部分。初步数据还表明，多巴胺在小鼠视网膜对变化照明的适应性反应中起着重要作用，这可能是通过cAMP依赖机制的。目前的目标是检验这些假设，从而阐明多巴胺对光感受器基因表达和在光适应过程中的视网膜表达和视网膜功能的影响。使用小鼠视网膜作为实验模型，我们将测试假设的以下预测：（1）感光细胞上的多巴胺D4受体调节信号传导途径的一个或多个成分的基因表达，以使光暴露于抑制cAMP合成。 （2）多巴胺D4受体缺乏小鼠的光感受器中功能失调的cAMP调节改变了光感受器基因表达谱和关键基因产物的翻译后修饰，例如凤凰素。 （3）多巴胺和光通过降低Ca 2+ /钙调蛋白刺激的腺苷循环酶的活性来降低光感受器cAMP的水平。 （4）Ca 2+ /钙调蛋白刺激的腺苷环酶（S）的表达降低导致多巴胺D4受体缺乏小鼠的光和暗适应异常。这些实验的结果将显着增强我们对多巴胺和cAMP如何调节光感受器功能，尤其是光和深色适应的理解。