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.

项目总结 现在清楚的是，哺乳动物的视网膜除了视杆和视神经外，至少还有一个其他的感光器类别。 视锥细胞，由表达黑色素的视网膜神经节细胞(RGC)亚群组成 (Opn4)和本质上是光敏的(IpRGC)。这些细胞主要投射到非表象视觉。 中心在大脑中，提供昼夜光携带和瞳孔光反射等功能。在 与此同时，ipRGC适度投射到大脑的图像-视觉中心，可能提供微妙的图像- 形成视觉功能，例如可能提供关于视觉中的绝对光强度的信息 场景。到目前为止，ipRGC包括6个亚型，M1-M6，它们的黑素水平不同 含量、感光性、体细胞和树突野的大小、树突分支的确切位置 视网膜的内丛状层，以及它们在各自大脑中轴突投射的详细位置 目标。 要全面了解ipRGC系统，了解它们的光响应特性和 潜在的机制。近年来，我们对M1-ipRGC的研究取得了很大进展， 包括光转导中几个关键成分的分子同一性，如GαQ亚家族 成员，PLCβ4酶和TRPC6，7通道。这些组件与中的组件非常相似 苍蝇眼光转导。最近，我们又有了另一个令人兴奋的发现 光信号转导通路，见于M2和M4-ipRGC。这一途径涉及光诱导的升高性 环核苷酸，开放HCN通道(由膜超极化和环 核苷酸)以产生膜去极化和动作电位。 这项申请是这些成功调查的继续。目标1是寻找一些 HCN-光转导途径的细节仍然悬而未决，包括建立(I)cGMP或 CAMP是第二信使，(Ii)控制第二信使的效应酶的特性， 和(Iii)HCN途径上游G蛋白的同源性。目标2是描述 M3-、M5-和M6-ipRGC的光传导机制(S)尚不清楚。我们的推测是， 这涉及到两条途径，但这需要核实。目标3是量化两者的相对重要性。 不同细胞亚型中的信号通路。我们将研究敏感度，强度-反应关系，单一的- 光子响应，以及每条路径的响应动力学，有望最终得出与 各亚型的宏观功能。