GPR37 and GPR37L1 are glia-enriched G protein-coupled receptors that have been implicated in several neurological and neurodegenerative diseases. To gain insight into the potential molecular mechanisms by which GPR37 and GPR37L1 regulate cellular physiology, proteomic analyses of whole mouse brain tissue from wild-type (WT) versus GPR37/GPR37L1 double knockout (DKO) mice were performed in order to identify proteins regulated by the absence versus presence of these receptors (data are available via ProteomeXchange with identifier PXD015202). These analyses revealed a number of proteins that were significantly increased or decreased by the absence of GPR37 and GPR37L1. One of the most decreased proteins in the DKO versus WT brain tissue was S100A5, a calcium-binding protein, and the reduction of S100A5 expression in KO brain tissue was validated via Western blot. Coexpression of S100A5 with either GPR37 or GPR37L1 in HEK293T cells did not result in any change in S100A5 expression but did robustly increase secretion of S100A5. To dissect the mechanism by which S100A5 secretion was enhanced, cells coexpressing S100A5 with the receptors were treated with different pharmacological reagents. These studies revealed that calcium is essential for the secretion of S100A5 downstream of GPR37 and GPR37L1 signaling, as treatment with BAPTA-AM, an intracellular Ca2+ chelator, reduced S100A5 secretion from transfected HEK293T cells. Collectively, these findings provide a panoramic view of proteomic changes resulting from loss of GPR37 and GPR37L1 and also impart mechanistic insight into the regulation of S100A5 by these receptors, thereby shedding light on the functions of GPR37 and GPR37L1 in brain tissue.

中文翻译：

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定量蛋白质组学揭示了缺乏 GPR37 和 GPR37L1 的小鼠脑组织中蛋白质表达模式的改变。

GPR37 和 GPR37L1 是富含胶质的 G 蛋白偶联受体，与几种神经和神经退行性疾病有关。为了深入了解 GPR37 和 GPR37L1 调节细胞生理学的潜在分子机制，对野生型 (WT) 与 GPR37/GPR37L1 双敲除 (DKO) 小鼠的整个小鼠脑组织进行蛋白质组学分析，以确定受这些受体的缺失与存在（数据可通过 ProteomeXchange 获得，标识符为 PXD015202）。这些分析揭示了由于缺乏 GPR37 和 GPR37L1 而显着增加或减少的许多蛋白质。与 WT 脑组织相比，DKO 脑组织中减少最多的蛋白质之一是 S100A5，一种钙结合蛋白，并且通过蛋白质印迹验证了 KO 脑组织中 S100A5 表达的降低。S100A5 与 GPR37 或 GPR37L1 在 HEK293T 细胞中的共表达不会导致 S100A5 表达的任何变化，但会显着增加 S100A5 的分泌。为了剖析 S100A5 分泌增强的机制，用不同的药理学试剂处理与受体共表达 S100A5 的细胞。这些研究表明，钙对于分泌 GPR37 和 GPR37L1 信号下游的 S100A5 至关重要，因为用 BAPTA-AM（一种细胞内 Ca2+ 螯合剂）处理可减少转染的 HEK293T 细胞的 S100A5 分泌。总的来说，这些发现提供了由 GPR37 和 GPR37L1 缺失引起的蛋白质组变化的全景图，并且还提供了对这些受体对 S100A5 调节的机制洞察力，