Melanopsin Photoreception and Signaling

黑视蛋白感光和信号传导

• 批准号: 10438306
• 负责人: KING-WAI YAU
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10438306
• 关键词: Action Potentials; Automobile Driving; Axon; Brain; Brain imaging; Cells; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Disease; Enzymes; Eye; GTP-Binding Proteins; Grant; Human; Image; Inner Plexiform Layer; Invertebrate Photoreceptors; Investigation; Kinetics; Light; Location; Measures; Membrane; Molecular; Pathway interactions; Photons; Photoreceptors; Photosensitivity; Phototransduction; Pigments; Property; Pupil light reflex; Reporting; Retina; Retinal Ganglion Cells; Second Messenger Systems; Signal Pathway; Signal Transduction; System; Time; Ursidae Family; Vertebrate Photoreceptors; Vision; Visual; circadian; density; fly; light intensity; melanopsin; member; neural circuit; response; success

PROJECT SUMMARY It is now clear that the mammalian retina has at least one other photoreceptor class besides rods and cones, consisting of a subpopulation of retinal ganglion cells (RGCs) that express the pigment melanopsin (OPN4) and are intrinsically photosensitive (ipRGCs). These cells project predominantly to non-image-vision centers in the brain, serving functions such as circadian photoentrainment and pupillary light reflex. At the same time, ipRGCs project moderately to the brain's image-vision centers, presumably serving subtle image- forming visual functions such as possibly providing information about absolute light intensity in the visual scene. IpRGCs are known so far to comprise 6 subtypes, M1-M6, which differ in the level of melanopsin content, photosensitivity, somatic and dendritic-field size, exact locations of their dendritic arborizations in the retina's inner plexiform layer, and the detailed locations of their axonal projections in the respective brain targets. To fully understand the ipRGC system, it is important to know their light-response properties and the underlying mechanisms. In recent years, we have made great progress in understanding M1-ipRGCs, including the molecular identities of several key components in phototransduction such as Gαq-subfamily members, the PLCβ4 enzyme and the TRPC6,7 channels. These components closely resemble those found in fly-eye phototransduction. Most recently, we have made the exciting discovery of yet another phototransduction pathway, found in M2- and M4-ipRGCs. This pathway involves a light-induced elevation of cyclic nucleotide, which opens HCN channels (channels gated by membrane hyperpolarization and cyclic nucleotide) to produce membrane depolarization and action potentials. This application constitutes a continuation of these successful investigations. Aim 1 is to seek some details of the HCN-phototransduction pathway still outstanding, including establishing (i) whether cGMP or cAMP is the second messenger, (ii) the identity of the effector enzyme that controls the second messenger, and (iii) the identity of the G protein upstream of the HCN-pathway. Aim 2 is to characterize the phototransduction mechanism(s) still unknown in M3-, M5- and M6-ipRGCs. Our speculation is that the same two pathways are involved, but this requires verification. Aim 3 is to quantify the relative importance of the two signaling pathways in different cell subtypes. We shall study sensitivity, intensity-response relation, single- photon response, and response kinetics of each pathway, hopefully eventually to derive correlations with the respective subtype's macroscopic functions.

项目概要 现在已经清楚，除了视杆细胞和视杆细胞之外，哺乳动物的视网膜至少还有一种其他感光细胞。 视锥细胞，由表达色素黑视蛋白的视网膜神经节细胞 (RGC) 亚群组成 (OPN4) 且具有本质光敏性 (ipRGC)。这些细胞主要投射非图像视觉 大脑中枢，发挥昼夜节律光诱导和瞳孔光反射等功能。在 同时，ipRGC 适度投射到大脑的图像视觉中心，大概服务于微妙的图像- 形成视觉功能，例如可能提供有关视觉中绝对光强度的信息 场景。迄今为止已知 IpRGC 包含 6 个亚型，M1-M6，其黑视蛋白水平不同 含量、光敏性、体细胞和树突域大小、树突状树枝化的确切位置 视网膜的内丛状层，以及它们在各自大脑中的轴突投影的详细位置 目标。 要充分了解 ipRGC 系统，了解其光响应特性和光响应特性非常重要。 底层机制。近年来，我们在理解M1-ipRGCs方面取得了很大进展， 包括光转导中几个关键成分的分子特性，例如 Gαq 亚家族 成员，PLCβ4 酶和 TRPC6,7 通道。这些成分与中发现的成分非常相似 蝇眼光转导。最近，我们有了另一个令人兴奋的发现 光转导途径，存在于 M2- 和 M4-ipRGC 中。该途径涉及光诱导的升高 环核苷酸，可打开 HCN 通道（由膜超极化和循环门控的通道） 核苷酸）产生膜去极化和动作电位。 该申请是这些成功调查的延续。目标1是寻求一些 HCN-光转导途径的细节仍然悬而未决，包括确定 (i) cGMP 或 cAMP 是第二信使，(ii) 控制第二信使的效应酶的身份， (iii) HCN 途径上游 G 蛋白的身份。目标 2 是表征 M3-、M5- 和 M6-ipRGC 中的光转导机制仍然未知。我们的猜测是相同的 涉及两条途径，但这需要验证。目标 3 是量化两者的相对重要性 不同细胞亚型的信号通路。我们将研究灵敏度、强度-反应关系、单 光子响应以及每个路径的响应动力学，希望最终能够得出与 各个子类型的宏观功能。