ASIC1a channel and activation of ERK pathway

LIBIA CATALINA SALINAS CASTELLANOS; RODOLFO GATTO; OSVALDO D. UCHITEL; CARINA WEISSMANN

Carlos Paz

Congreso; Reunión Anual de la SAN 2019; 2019

SAN

ASIC (Acid sensing Ion) channels are sodium channels activated by tissue acidosis and thus become active in many pathological conditions. ASIC1 is the most abundant ASIC subunit in the mammalian central nervous system. Physiologically, its activation is related to synaptic plasticity, learning and memory. ASIC1 channels in particular permeate not only sodium but slightly calcium ions, and so can contribute to intracellular calcium levels and neuronal injury in pathological conditions. Changes in regional pH levels in the brain have been observed in a number of neurological and neurodegenerative disorders and this event could lead to channel activation. In fact, ASIC1 channels have been lately implicated in several neurological diseases, as blocking this channel improves models of cerebral ischemia, Parkinson´s disease, Huntington´s disease (HD) and ALS. Recently, amiloride ?an ASIC channel blocker- was able to reduce poly-Q expanded huntingtin (PolyQ-Htt) aggregates in cell lines and alleviate the pathology in HD mice models, reported to occur via an ubiquitin-proteasome mechanism (Wong et al. 2008). We decided to analyse the pathways activated by the channel.We used HEK cell lines and mouse primary neurons and analysed the ERK pathway. We showed, by using an ASIC agonist (Mittx 25 nM for 3 min), and inhibitors (amiloride, or psalmotoxin) that ASIC activation leads to the activation of the ERK pathway, via phosphorylation of ERK1 and ERK2 isoforms and translocation of the phosphorylated isoforms to the nucleus. Establishing the exact role of ASIC1 in HD pathology could lead the way to therapies with specific channel blockers.