ASIC1a channel are upregulated by Fabry Disease accumulation of sphingolipids

OSVALDO D. UCHITEL; CASTELLANOS, LIBIA CATALINA SALINAS; ROZENFELD, PAULA; REISIN, RICARDO; GATTO, RODOLFO G.; CARINA WEISSMANN

Orlando

Simposio; World Symposia 2020; 2020

Neuropathic pain is one of the key features of the classical phenotype of Fabry disease. Acid sensing ion channels (ASICs) are implicated in a variety of pathological conditions such as neurotoxicity following ischemia, anxiety and painH+-(Wemmie, Taugher, & Kreple, 2013)(Wu et al., 2004)(Mazzuca et al., 2007). ASICs aregated cation channels, which belong to the epithelial sodium channel/DeGenerin superfamily, sensitive to the diuretic Amiloride. Molecularcloning has identified several distinct ASIC subunits (Hanukoglu, 2017). Most of the ASIC subtypes are expressed on nociceptive primary sensory neurons, where they seem to play a significant role in pain transduction andfurthermore, they may act as key mediators of neuropathic pain related to inflammation (Wu et al., 2004)(Mazzuca et al., 2007)(Duan et al., 2007). Upregulation of ASIC channels has been documented in many pathological conditions.We analyzed the expression of ASIC1a channels in models that mimic the accumulation of sphingolipids. We used HEK293 cells; as well as mouse primary cortical and hippocampal cultures, areas that have been reported toaccumulate sphingolipids (Kummer, Kalpachidou, Mitric, Langeslag, & Kress, 2018). We have shown that treatment with Gb3, lysoGb3 and the inhibitor of the enzyme a-galactosidase A (1-deoxy-galactonojirymicin, DJG) inducedaccumulation of sphingolipids, and an increase in endogenous ASIC1a channels identified by immunocytochemistry and western blots. Furthermore, activation of ASIC results in activation of the MAPK ERK pathway, a signalingpathway associated with pain ((Cruz & Cruz, 2007)). Activation of ERK was prevented by the presence of Psalmotoxin a specific blocker of ASIC1a. Our results suggest that ASIC channels participate in the mechanism responsible ofpain in FD thus providing a new therapeutic target for pain relief treatment