CALCIUM AND ADAPTATION IN MAMMALIAN CONE PHOTORECEPTORS

描述（申请人提供）：视锥细胞光感受器在日光条件下发挥作用，对高时空分辨率的色彩感知和视觉至关重要。视锥细胞的一个显著特征是它们能够在明亮的光线下保持功能，这需要它们强大的光传导级联适应机制。在杆状细胞中，光适应是由钙介导的，光激活时钙的减少调节光导的机制已经很好地理解了。虽然光激活也会引发视锥细胞中钙含量的下降，但这对视锥细胞光传导产生负反馈的分子机制尚不清楚。本文描述的实验将采用现有转基因小鼠的生理研究来研究钙对锥体光传导级联的调节机制。具体来说，我们将验证一个假设，即视紫红质激酶通过恢复蛋白对视色素磷酸化的调节是小鼠视锥细胞钙反馈的一个组成部分，并调节它们在黑暗和光适应过程中的光导。我们还将验证一种假设，即通过关苷基环化酶激活蛋白（GCAPs）调节关苷基环化酶合成cGMP是小鼠视锥细胞钙反馈的主要组成部分，并调节它们在黑暗和光适应过程中的光导。总之，这些实验将帮助我们确定允许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，即使在强光下也是如此。

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.