Melanopsin Photoreception and Signaling

黑视蛋白感光和信号传导

• 批准号: 9353967
• 负责人: KING-WAI YAU
• 金额: $ 21.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353967
• 关键词: Action Potentials; Arrestins; Binding; Brain; Cells; Data; Disease; GTP-Binding Proteins; Goals; Grant; Health; Human; Image; Inner Plexiform Layer; Investigation; Kinetics; Learning; Light; Light Adaptations; Location; Measures; Membrane; Molecular; Phosphorylation; Photons; Photoreceptors; Photosensitivity; Phototransduction; Physiological; Population; Process; Retina; Retinal Ganglion Cells; Retinal Pigments; Signal Transduction; System; Translating; Vertebrate Photoreceptors; Vision; biophysical analysis; density; immunoreactivity; melanopsin; receptor; response; success

In recent years, a photoreceptor system besides rods and cones has been discovered in the mammalian retina, consisting of a sub-population of retinal ganglion cells that express the visual pigment, melanopsin, and are intrinsically-photosensitive (ipRGCs). These ipRGCs comprise distinct subtypes. M1 cells have the strongest melanopsin-immunoreactivity, the highest intrinsic photosensitivity, and the largest saturated light response. M2 and M3 cells have weaker melanopsin-immunoreactivities, lower photosensitivities, and much smaller saturated light responses. M1, M2 and M3 cells also differ in the location of their dendritic arborizations in the inner plexiform layer of the retina. IpRGCs project predominantly to nonimage- vision centers in the brain (e.g., most M1 cells), but they also project moderately to image-vision centers (e.g., many M2 cells). Finally, there are supposedly M4 and M5 ipRGCs, but these are not detectable with melanopsin-immunoreactivity, and have extremely low photosensitivities and small light responses. This proposal deals only with M1-M3 ipRGCs, which may have differential functions with respect to both non-image and image vision. In order to fully understand the melanopsin system, it is important to know in detail the ipRGCs’ light responses and their underlying mechanisms. We have recently carried out extensive physiological/biophysical studies of M1 cells, and succeeded in resolving their single-photon response, estimating their melanopsin density, and molecularly identifying some of their key phototransduction components. This grant will be a continuation of these successful investigations. Aim 1 is to study M2 and M3 ipRGCs with respect to their intensity-response relations, response kinetics, single-photon-responses, membrane melanopsin densities, and their light-signaling thresholds, with the overall goal of comparing/contrasting M1, M2 and M3 cells. Aim 2 is to identify additional molecular components of phototransduction across M1, M2 and M3 cells, including the signaling G protein. We shall also examine the gating mechanism for the TRPC channels underlying the light response. Aim 3 is to begin to understand the termination mechanisms for the ipRGC’s light response, including the significance of potential melanopsin phosphorylation, arrestin binding to melanopsin, and Gprotein deactivation. Aim 4 is to study how M1, M2 and M3 ipRGCs adapt to steady light, and how this adaptation in the receptor current translates into action-potential firing and therefore signaling to the brain. We shall also investigate the involvement of Ca2+ in light adaptation. In summary, ipRGCs are the only known non-rod/non-cone photoreceptors in the mammalian retina. They are important for non-image vision and apparently also for subtle aspects of image vision. Therefore, learning in detail how they function is of fundamental importance to vision in both health and disease.

近年来，除了杆和锥体以外的光感受器系统已被发现 哺乳动物视网膜，由表达视觉色素的视网膜神经节细胞的亚群体组成， 黑色素蛋白，并且本质上是敏感的（IPRGC）。这些IPRGC包括不同的亚型。 M1细胞 具有强烈的黑色素 - 免疫反应性，最高的内在光敏性和最大的 饱和光响应。 M2和M3细胞的黑色素蛋白 - 免疫反应性较弱，较低 光敏性和较小的饱和光反应。 M1，M2和M3细胞在该位置也有所不同 它们在视网膜的内部丛状层中的树突状作用。 IPRGCS项目主要针对非图像 视觉中心在大脑中（例如，大多数M1单元），但它们也适中投影到图像视觉中心 （例如，许多M2细胞）。最后，有望有M4和M5 IPRGC，但这些都无法检测到 黑素蛋白 - 免疫反应性，具有极低的光含量和较小的光反应。这 提案仅处理M1-M3 IPRGC，这可能相对于非图像具有不同的功能 和图像视觉。 为了完全了解黑色素蛋白系统，重要的是要详细了解IPRGC的光线 反应及其基本机制。我们最近进行了广泛的物理/生物物理 M1细胞的研究，并成功解决了单光子反应，估计了它们的黑色素蛋白 密度和分子鉴定其一些关键的光转传成分。这笔赠款将是 这些成功的调查继续。目标1是研究M2和M3 IPRGC 强度反应关系，反应动力学，单光子反应，膜黑色素密度， 以及它们的光信号阈值，其总体目标是比较/对比M1，M2和M3细胞。目标2 是确定在M1，M2和M3细胞中光转导的其他分子成分，包括 信号G蛋白。我们还将检查光线下的TRPC通道的门控机制 回复。 AIM 3是开始了解IPRGC光响应的终止机制， 包括潜在的黑色素磷酸化，抑制蛋白与黑色素蛋白和gprotein的意义 停用。 AIM 4是研究M1，M2和M3 IPRGC如何适应稳定的光以及如何适应 接收器电流中的适应性转化为动作电位的触发，因此向大脑发出信号。我们 还应研究Ca2+在光适应中的参与。 总而言之，IPRGC是哺乳动物视网膜中唯一已知的非杆/非锥形感受器。 它们对于非图像视觉很重要，显然对于图像视觉的细微方面也很重要。所以， 详细学习它们的功能对健康和疾病的视力至关重要。