Adhesion GPCRs are important regulators of conserved developmental processes and represent an untapped pool of potential targets for drug discovery. The adhesion GPCR Adgrg6 (Gpr126) has critical developmental roles in Schwann cell maturation and inner ear morphogenesis in the zebrafish embryo. Mutations in the human ADGRG6 gene can result in severe deficits in peripheral myelination, and variants have been associated with many other disease conditions. Here, we review work on the zebrafish Adgrg6 signaling pathway and its potential as a disease model. Recent advances have been made in the analysis of the structure of the Adgrg6 receptor, demonstrating alternative structural conformations and the presence of a conserved calcium‐binding site within the CUB domain of the extracellular region that is critical for receptor function. Homozygous zebrafish adgrg6 hypomorphic mutants have been used successfully as a whole‐animal screening platform, identifying candidate molecules that can influence signaling activity and rescue mutant phenotypes. These compounds offer promise for further development as small molecule modulators of Adgrg6 pathway activity.

中文翻译：

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粘附 GPCR Adgrg6 (Gpr126)：来自斑马鱼模型的见解

粘附 GPCR 是保守发育过程的重要调节剂，代表了尚未开发的药物发现潜在靶标库。粘附 GPCR Adgrg6 (Gpr126) 在斑马鱼胚胎的雪旺细胞成熟和内耳形态发生中具有关键的发育作用。人类ADGRG6的突变基因可导致外周髓鞘形成严重缺陷，并且变异与许多其他疾病状况有关。在这里，我们回顾了斑马鱼 Adgrg6 信号通路的工作及其作为疾病模型的潜力。最近在分析 Adgrg6 受体结构方面取得了进展，证明了替代的结构构象以及在对受体功能至关重要的细胞外区域的 CUB 结构域内存在一个保守的钙结合位点。纯合斑马鱼adgrg6亚型突变体已成功用作全动物筛选平台，可识别可影响信号活性和拯救突变表型的候选分子。这些化合物为进一步开发作为 Adgrg6 通路活性的小分子调节剂提供了希望。