Neuromodulators and Signaling Cascades in Retina

描述（由申请人提供）：光感受器细胞是视觉系统的初级感觉神经元。除了受光调节之外，光感受器生理学的各个方面还受到神经调节剂的控制，例如多巴胺、腺苷、生长抑素和一氧化氮。支持这些物质在感光细胞功能中的作用的大部分数据本质上是药理学的，从非哺乳动物脊椎动物中获得，并且关于所涉及的信号传导机制还有很多有待了解。我们在小鼠中的初步数据导致了这样的假设，即多巴胺，作用于多巴胺D4受体，通过Ca 2+依赖性调节腺苷酸环化酶和调节信号级联的基因表达来调节光感受器细胞中的cAMP代谢，该信号级联将光照与cAMP形成的抑制联系起来。初步数据还表明，多巴胺在小鼠视网膜对光照变化的适应性反应中起着重要作用，可能是通过cAMP依赖性机制。目前的目标是测试这些假设，从而阐明信号转导机制，多巴胺产生的光和暗适应过程中的感光细胞基因表达和视网膜功能的影响。使用小鼠视网膜作为实验模型，我们将测试以下假设的预测：（1）光感受器细胞上的多巴胺D4受体调节信号通路中一个或多个组分的基因表达，该信号通路将光暴露与cAMP合成的抑制结合起来。(2)多巴胺D4受体缺陷小鼠光感受器中cAMP调节功能障碍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，如p53 ducin。(3)多巴胺和光通过降低Ca 2+ /钙调素刺激的腺苷酸环化酶的活性来降低光感受器cAMP水平。(4)在多巴胺D4受体缺陷小鼠中，Ca 2+ /钙调素刺激的腺苷酸环化酶表达减少导致了光适应和暗适应的异常。这些实验的结果将显著增强我们对多巴胺和cAMP如何调节光感受器功能，特别是光适应和暗适应的理解。

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.