CALCIUM AND ADAPTATION IN MAMMALIAN CONE PHOTORECEPTORS

描述（由申请人提供）：锥状光感受器在日光条件下起作用，并且对于具有高时间和空间分辨率的颜色感知和视觉至关重要。视锥细胞的一个显著特征是它们在强光下保持功能的能力，这需要它们的光转导级联的强大适应机制。在视杆细胞中，光适应是由钙介导的，并且光激活时钙的减少调节光转导的机制是很好理解的。虽然光活化也引发视锥细胞中钙的下降，但这对视锥细胞光转导施加负反馈的分子机制尚不清楚。本文所述的实验将采用来自可用的遗传修饰小鼠的生理学研究来研究钙对视锥光转导级联的调节机制。具体来说，我们将测试的假设，视紫红质激酶通过recoverin调节视色素磷酸化是一个组件的钙反馈在小鼠视锥细胞和调制他们的光转导在黑暗中，在光适应。我们还将测试的假设，通过鸟苷酸环化酶激活蛋白（GCAPs）的鸟苷酸环化酶的cGMP合成的调节是在小鼠视锥细胞中的钙反馈的一个主要组成部分，并调节其在黑暗中的光转导和在光适应。总之，这些实验将帮助我们确定使视锥细胞适应非常广泛的光强度并在一天中保持功能的机制，即使在明亮的光线下。 公共卫生相关性：本提案中概述的实验旨在建立使哺乳动物视锥细胞在明亮光线下发挥作用的机制，这是介导白天视觉的光感受器的基本特性。这些研究将有助于我们了解正常和病理条件下钙在调节哺乳动物视锥细胞功能中的作用。

DESCRIPTION (provided by applicant): Cone photoreceptors function under daylight conditions and are essential for color perception and vision with high temporal and spatial resolution. A remarkable feature of cones is their ability to remain functional in bright light which requires powerful adaptation mechanisms of their phototransduction cascade. In rods, light adaptation is mediated by calcium and the mechanisms by which reduction in calcium upon photo-activation modulates phototransduction are well understood. While photo-activation also triggers a decline in calcium in cones, the molecular mechanisms by which this exerts negative feedback on cone phototransduction are not known. The experiments described here will employ physiological studies from available genetically modified mice to investigate the mechanisms of modulation of the cone phototransduction cascade by calcium. Specifically, we will test the hypothesis that regulation of visual pigment phosphorylation by rhodopsin kinase via recoverin is a component of the calcium feedback in mouse cones and modulates their phototransduction in darkness and during light adaptation. We will also test the hypothesis that regulation of cGMP synthesis by guanylyl cyclase via Guanylyl Cyclase Activating Proteins (GCAPs) is a major component of the calcium feedback in mouse cones and modulates their phototransduction in darkness and during light adaptation. Together, these experiments will help us determine the mechanisms that allow cones to adapt to a very wide range of light intensities and remain functional throughout the day, even in bright light. PUBLIC HEALTH RELEVANCE: The experiments outlined in this proposal seek to establish the mechanisms that enable mammalian cones to function in bright light, an essential property for the photoreceptors that mediate daytime vision. These studies will help us understand the role of calcium in regulating mammalian cone function under normal and pathological conditions.