The orphan G-protein coupled receptor GPR179 is a new player in night vision

孤儿G蛋白偶联受体GPR179是夜视领域的新玩家

• 批准号: 317150427
• 负责人: Professor Dr. Ralf Enz
• 金额: --
• 依托单位: Professur für Biochemie und Medizinische Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/317150427?language=en
• 关键词: orphan; protein; coupled; receptor; GPR179

Our visual perception is remarkable stable, despite the high variability of detected light intensities by the retina, ranging form daylight (photopic) to night (scotopic) vision. This stability is mainly ensured by distinct signal pathways for scotopic and photopic vision, and by the expression of specific proteins therein. Here, we will elucidate proteins and molecular mechanisms that contribute to scotopic vision of the mammalian retina and that are altered in congenital stationary night blindness (CSNB). Scotopic vision starts with rod photoreceptors that transmitt their signals onto the highly specialized G-protein coupled metabotropic glutamate receptor type 6 (mGluR6) expressed in the dendritic tips of ON-bipolar cells. Upon activation, mGluR6 closes the non-selective cation channel TRPM1 via G-protein signalling involving Gao and RGS7. Surprisingly, despite the above described knowledge, identity, function and regulation of proteins involved in scotopic are still enigmatic. This has been demonstrated recently with the identification of a new player for this pathway: The orphan G-protein coupled receptor GPR179. GPR179 interacts and perfectly co-localizes with mGluR6, TRPM1 and RGS7. Indeed, mutations in all these proteins are associated with CSNB. Interestingly, while mGluR6 contains the shortest C-terminus of all mGluRs (32 amino acids = 3.6% of the entire receptor), the GPR179 C-terminus is extremely long (1738 amino acids = 73%), potentially offering a huge variety of binding sites for regulatory proteins. Preliminary analysis showed that the long GPR179 C-terminus does not contain conserved domains or stable room structures. Rather, this C-terminus is unstructured and contains over 80 short linear sequence motifs, pointing towards a variety of interactions with proteins that regulate GPR179. Based on the described data we hypothesize that GPR179 is the central component of a synaptically localized signal complex that organizes proteins in scotopic vision, both in space and time. While localization and physiological functions of GPR179 were elucidated in recent years, data characterizing the interaction between GPR179, mGluR6 and TRPM1 are largely missing. Also, the identity of additional GPR179 binding proteins that regulate this orphan receptor are unknown. Here, we will analyse molecular mechanisms of the reported binding between GPR179, mGluR6, TRPM1 and RGS7, thereby providing molecular tools and mechanistic knowledge for successive functional studies. In parallel, we will identify and characterize new GPR179 interactors potentially involved in scotopic vision. Finally, we will investigate functional consequences of the analysed protein interactions. Our studies will elucidate composition and functions of GPR179 associated signal complexes, thereby describe new molecular mechanisms relevant for CSNB.

我们的视觉感知是非常稳定的，尽管视网膜检测到的光强度的高度可变性，从白天（明视）到夜间（暗视）视觉。这种稳定性主要通过暗视觉和明视觉的不同信号通路以及其中特定蛋白质的表达来确保。在这里，我们将阐明蛋白质和分子机制，有助于暗视觉的哺乳动物视网膜和改变先天性静止性夜盲症（CSNB）。暗视觉开始于视杆细胞，视杆细胞将其信号传递到在ON双极细胞的树突尖端中表达的高度特化的G蛋白偶联的代谢型谷氨酸受体6型（mGluR 6）上。激活后，mGluR 6通过涉及Gao和RGS 7的G蛋白信号传导关闭非选择性阳离子通道TRPM 1。令人惊讶的是，尽管有上述知识，但涉及暗视的蛋白质的身份、功能和调节仍然是谜。这一点最近已经通过识别该途径的新参与者得到了证明：孤儿G蛋白偶联受体GPR 179。GPR 179与mGluR 6、TRPM 1和RGS 7相互作用并完美共定位。事实上，所有这些蛋白质的突变都与CSNB有关。有趣的是，虽然mGluR 6包含所有mGluR中最短的C-末端（32个氨基酸=整个受体的3.6%），但GPR 179 C-末端非常长（1738个氨基酸= 73%），可能为调节蛋白提供各种各样的结合位点。初步分析表明，长GPR 179的C-末端不包含保守的结构域或稳定的房间结构。相反，这个C-末端是非结构化的，包含超过80个短的线性序列基序，指向与调节GPR 179的蛋白质的各种相互作用。基于所描述的数据，我们假设GPR 179是在空间和时间上在暗视觉中组织蛋白质的突触局部化信号复合物的中心组分。虽然GPR 179的定位和生理功能近年来得到了阐明，但表征GPR 179，mGluR 6和TRPM 1之间相互作用的数据在很大程度上缺失。此外，调节这种孤儿受体的其他GPR 179结合蛋白的身份是未知的。在这里，我们将分析GPR 179，mGluR 6，TRPM 1和RGS 7之间的结合的分子机制，从而为后续的功能研究提供分子工具和机制知识。同时，我们将确定和表征新的GPR 179相互作用可能涉及暗视觉。最后，我们将研究分析的蛋白质相互作用的功能后果。我们的研究将阐明GPR 179相关信号复合物的组成和功能，从而描述CSNB相关的新分子机制。