CALCIUM AND ADAPTATION IN MAMMALIAN CONE PHOTORECEPTORS

描述(申请人提供)：视锥感光器在白天条件下工作，对具有高时间和空间分辨率的颜色感知和视觉是必不可少的。锥体的一个显着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。在杆状体内，光适应是由钙介导的，光激活时钙的减少调制光转导的机制是众所周知的。虽然光激活也会触发视锥细胞内钙离子的下降，但这对视锥细胞光转导产生负反馈的分子机制尚不清楚。这里描述的实验将利用现有的转基因小鼠的生理学研究来研究钙对锥体光转导级联的调节机制。具体地说，我们将测试这样一种假设，即视紫红质激酶通过恢复素调节视觉色素磷酸化是小鼠视锥细胞钙反馈的一个组成部分，并在黑暗和光照适应期间调节它们的光转导。我们还将验证一种假设，即鸟苷酸环化酶通过鸟苷酸环化酶激活蛋白(GCAPs)调节cGMP的合成是小鼠视锥细胞钙反馈的主要组成部分，并在黑暗和光适应期间调节它们的光转导。总之，这些实验将帮助我们确定使锥体适应非常广泛的光强度并在一天中保持功能的机制，即使在强光下也是如此。 与公共健康相关：这项提案中概述的实验试图建立使哺乳动物视锥细胞在明亮的光线下发挥作用的机制，这是调节白天视力的光感受器的基本特性。这些研究将有助于我们理解钙在正常和病理条件下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.