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，人们在视杆细胞和视锥细胞之外发现了一种感光系统。 哺乳动物视网膜，由表达视觉色素的视网膜神经节细胞亚群组成， 这些 ipRGC 包含不同的 M1 细胞亚型。 具有最强的黑视蛋白免疫反应性、最高的内在光敏性和最大的 M2 和 M3 细胞的黑视蛋白免疫反应性较弱，较低。 M1、M2 和 M3 细胞的光敏感性和更小的饱和光响应也因位置而异。 视网膜内丛状层中的树突状树枝状结构主要投射到非图像。 大脑中的视觉中心（例如大多数 M1 细胞），但它们也适度投射到图像视觉中心 （例如，许多 M2 细胞）。最后，还有假定的 M4 和 M5 ipRGC，但这些无法用 M4 和 M5 ipRGC 检测到。 黑视蛋白免疫反应性，并且具有极低的光敏性和较小的光响应。 提案仅涉及 M1-M3 ipRGC，其对于非图像可能具有不同的功能 和图像视觉。 为了充分了解黑视蛋白系统，详细了解 ipRGC 的光非常重要 我们最近进行了广泛的生理/生物物理研究。 对 M1 细胞的研究，并成功解决了它们的单光子响应，估计了它们的黑视蛋白 密度，并从分子上鉴定其一些关键的光转导成分。这笔资助将是一项。 目标 1 是研究 M2 和 M3 ipRGC 的延续。 强度响应关系、响应动力学、单光子响应、膜黑视蛋白密度、 及其光信号阈值，总体目标是比较/对比 M1、M2 和 M3 细胞 Aim 2。 的目的是识别 M1、M2 和 M3 细胞光转导的其他分子成分，包括 我们还将检查光下 TRPC 通道的门控机制。 目标 3 是开始了解 ipRGC 光响应的终止机制， 包括潜在黑视蛋白磷酸化、视紫红质抑制蛋白与黑视蛋白结合以及 G 蛋白的重要性 目标 4 是研究 M1、M2 和 M3 ipRGC 如何适应稳定的光照。 受体电流的适应转化为动作电位放电，从而向大脑发出信号。 还应研究 Ca2+ 在光适应中的参与。 总之，ipRGC 是哺乳动物视网膜中唯一已知的非杆状/非锥状感光器。 它们对于非图像视觉很重要，显然对于图像视觉的微妙方面也很重要。 详细了解它们的功能对于健康和疾病中的视力至关重要。