Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA.
Faculty of Dental Medicine and Oral Health Sciences, Department of Anesthesia, Faculty of Medicine and Health Science, Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
J Clin Invest. 2024 Mar 26;134(9):e173537. doi: 10.1172/JCI173537.
G protein-coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR with largely unknown functions. Here, we report that Gpr37l1/GRP37L1 ranks among the most highly expressed GPCR transcripts in mouse and human dorsal root ganglia (DRGs) and is selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy induced by streptozotoxin (STZ) and paclitaxel (PTX) led to reduced GPR37L1 expression on the plasma membrane in mouse and human DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptoms following PTX- and STZ-induced pain, whereas overexpression of Gpr37l1 in mouse DRGs reversed pain. GPR37L1 is coexpressed with potassium channels, including KCNJ10 (Kir4.1) in mouse SGCs and both KCNJ3 (Kir3.1) and KCNJ10 in human SGCs. GPR37L1 regulates the surface expression and function of the potassium channels. Notably, the proresolving lipid mediator maresin 1 (MaR1) serves as a ligand of GPR37L1 and enhances KCNJ10- or KCNJ3-mediated potassium influx in SGCs through GPR37L1. Chemotherapy suppressed KCNJ10 expression and function in SGCs, which MaR1 rescued through GPR37L1. Finally, genetic analysis revealed that the GPR37L1-E296K variant increased chronic pain risk by destabilizing the protein and impairing the protein's function. Thus, GPR37L1 in SGCs offers a therapeutic target for the protection of neuropathy and chronic pain.
G 蛋白偶联受体 37 样 1（GPR37L1）是一种孤儿 GPCR，其功能尚不清楚。在这里，我们报告 Gpr37l1/GRP37L1 是小鼠和人背根神经节（DRG）中表达最高的 GPCR 转录本之一，并且选择性地表达在卫星胶质细胞（SGCs）中。链脲佐菌素（STZ）和紫杉醇（PTX）引起的周围神经病导致小鼠和人 DRG 中 GPR37L1 表达的质膜减少。Gpr37l1 基因缺失的转基因小鼠在紫杉醇和 STZ 诱导的疼痛后，神经病理性疼痛症状的缓解受损，而 Gpr37l1 在小鼠 DRG 中的过表达则逆转了疼痛。GPR37L1 与钾通道共表达，包括小鼠 SGCs 中的 KCNJ10（Kir4.1）和人 SGCs 中的 KCNJ3 和 KCNJ10。GPR37L1 调节钾通道的表面表达和功能。值得注意的是，促分解脂质介质maresin 1（MaR1）是 GPR37L1 的配体，通过 GPR37L1 增强 SGCs 中 KCNJ10 或 KCNJ3 介导的钾内流。化学疗法抑制 SGCs 中的 KCNJ10 表达和功能，MaR1 通过 GPR37L1 恢复其功能。最后，遗传分析表明，GPR37L1-E296K 变体通过使蛋白质不稳定并损害蛋白质的功能增加了慢性疼痛的风险。因此，SGCs 中的 GPR37L1 为保护神经病变和慢性疼痛提供了治疗靶点。
