Melanopsin Photoreception and Signaling

黑视蛋白感光和信号传导

• 批准号: 10630285
• 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/10630285
• 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; Vertebrate Photoreceptors; Vision; Visual; absorption; 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.

项目摘要 现在很明显，哺乳动物视网膜除杆和 锥，由表达色素黑色素蛋白的视网膜神经节细胞（RGC）的亚群组成 （OPN4）并且具有内在的光敏性（IPRGC）。这些细胞主要投射到非图像视频 中心在大脑中，服务功能，例如昼夜节律仪和瞳孔光反射。在 同一时间，IPRGCS适度地向大脑的图像视觉中心进行项目，大概可以提供微妙的图像 - 形成视觉功能，例如提供有关视觉中绝对光强度的信息 场景。到目前为止，IPRGC已知可以完成6个亚型M1-M6，这在黑色素蛋白水平上的差异 内容，光敏度，体细胞和树突状大小，其树突状养护的确切位置 视网膜的内部丛状层，以及其轴突投影的详细位置 目标。 为了充分了解IPRGC系统，重要的是要了解它们的光响应属性和 基本机制。近年来，我们在理解M1-IPRGC方面取得了巨大进展， 包括光转传中的几个关键成分的分子身份，例如GαQ-囊肿 成员，PLCβ4酶和TRPC6,7通道。这些组件与发现的组件非常相似 蝇眼光转导。最近，我们使另一个令人兴奋的发现 在M2和M4-IPRGC中发现的光转导通路。该途径涉及光引起的高程 循环核苷酸，该核苷酸打开HCN通道（通过膜超极化和循环的通道门控 核苷酸）产生膜去极化和作用电位。 该应用程序构成了这些成功调查的延续。目标1是寻求一些 HCN-Photottransduction途径的详细信息仍在未出现，包括（i）是CGMP或 营地是第二个使者，（ii）控制第二使者的效应酶的身份， （iii）HCN-Pathway上游G蛋白的身份。目标2是表征 在M3-，M5-和M6-IPRGC中，光转传的机制仍然未知。我们的猜测是相同 涉及两种途径，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 - 响应关系，单次 光子响应和每种途径的响应动力学，希望最终导致与 主要亚型的宏观功能。

项目成果

Intrinsically photosensitive retinal ganglion cells.

• DOI: 10.1152/physrev.00013.2010
• 发表时间: 2010-10
• 期刊: Physiological reviews
• 影响因子: 33.6
• 作者: Do MT;Yau KW
• 通讯作者: Yau KW

Synergistic Signaling by Light and Acetylcholine in Mouse Iris Sphincter Muscle.

• DOI: 10.1016/j.cub.2017.05.022
• 发表时间: 2017-06-19
• 期刊: Current biology : CB
• 作者: Wang Q;Yue WWS;Jiang Z;Xue T;Kang SH;Bergles DE;Mikoshiba K;Offermanns S;Yau KW
• 通讯作者: Yau KW

Tracer coupling of intrinsically photosensitive retinal ganglion cells to amacrine cells in the mouse retina.

• DOI: 10.1002/cne.22490
• 发表时间: 2010-12-01
• 期刊: JOURNAL OF COMPARATIVE NEUROLOGY
• 影响因子: 2.5
• 作者: Muller, Luis Perez de Sevilla;Do, Michael Tri H.;Yau, King-Wai;He, Shigang;Baldridge, William H.
• 通讯作者: Baldridge, William H.

Molecular determinants of response kinetics of mouse M1 intrinsically-photosensitive retinal ganglion cells.

• DOI: 10.1038/s41598-021-02832-9
• 发表时间: 2021-12-06
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Sheng Y;Chen L;Ren X;Jiang Z;Yau KW
• 通讯作者: Yau KW