Upregulation of ASIC1a channels in an in vitro model of Fabry disease. (November 2020)

• Record Type: Journal Article
• Authors: Castellanos, Libia Catalina Salinas; Rozenfeld, Paula; Gatto, Rodolfo Gabriel; Reisin, Ricardo Claudio; Uchitel, Osvaldo Daniel; Weissmann, Carina
• Is Part Of: Neurochemistry international. Volume 140(2020)
• Publication Date: 2020-11
• Subjects: ASIC1a -- Glycosphingolipids in fabry disease -- Psalmotoxon -- ERK; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2020.104824
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: 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. Highlights: ASIC1a protein and mRNA levels are upregulated via FD-associated glycosphingolipids. ASIC1a upregulation via FD-GLs is associated to increase in ERK-signaling pathway. Increase ERK signaling via FD-GLs can be prevented via ASIC1a inhibitors.