Neuropathic pain is one of the key features of the classical phenotype of Fabry disease (FD). Acid sensing ion channels (ASICs) are H⁺-gated cation channels, which belong to the epithelial sodium channel/DeGenerin superfamily, sensitive to the diuretic drug Amiloride. Molecular cloning has identified several distinct ASIC subunits. In particular the ASIC1a subunit has been associated to pain and its upregulation has been documented in animal models of pain. We analyzed the expression of ASIC1a channels in cellular models that mimic the accumulation of glycosphingolipids in FD (FD-GLs) like Gb3, and LysoGb3. We used mouse primary neurons from brain cortex and hippocampus -supraspinal structures that accumulate FD-GLs-, as well as HEK293 cells. Incubation with Gb3, lysoGb3 and the inhibitor (1-deoxy-galactonojirymicin, DJG) of the enzyme α-galactosidase A (Gla) lead to the upregulation of ASIC1a channels. In addition, activation of ASIC1a results in the activation of the MAPK ERK pathway, a signaling pathway associated with pain. Moreover, accumulation of glycosphingolipids results in activation of ERK, an effect that was prevented by blocking ASIC1a channels with the specific blocker Psalmotoxin. Our results suggest that FD-GLs accumulation and triggering of the ERK pathway via ASIC channels might be involved in the mechanism responsible for pain in FD, thus providing a new therapeutic target for pain relief treatment.

神经性疼痛是法布里病 (FD) 经典表型的主要特征之一。酸传感离子通道 (ASIC) 是 H ⁺-门控阳离子通道，属于上皮钠通道/DeGenerin 超家族，对利尿药物阿米洛利敏感。分子克隆已经确定了几个不同的 ASIC 亚基。特别是 ASIC1a 亚基与疼痛有关，其上调已在疼痛动物模型中得到证实。我们分析了 ASIC1a 通道在模拟 FD (FD-GLs) 中鞘糖脂积累的细胞模型中的表达，如 Gb3 和 LysoGb3。我们使用了来自大脑皮层和海马体的小鼠原代神经元 - 积累 FD-GLs 的脊髓上结构 - 以及 HEK293 细胞。与 Gb3、lysoGb3 和酶 α-半乳糖苷酶 A (Gla) 的抑制剂（1-脱氧-半乳糖苷酶，DJG）一起孵育导致 ASIC1a 通道的上调。此外，ASIC1a 的激活导致 MAPK ERK 通路的激活，这是一种与疼痛相关的信号通路。此外，鞘糖脂的积累会导致 ERK 的激活，这种作用通过用特定的阻断剂 Psalmotoxin 阻断 ASIC1a 通道来阻止。我们的研究结果表明，FD-GLs 的积累和通过 ASIC 通道触发 ERK 通路可能参与了 FD 疼痛的机制，从而为缓解疼痛提供了新的治疗靶点。