Redistribution of ASIC1a channels triggered by IL-6: Potential role of ASIC1a in neuroinflammation.

Cytokines, particularly IL-6, play a crucial role in modulating immune responses in the central nervous system (CNS). Elevated IL-6 levels have been observed in neuroinflammatory conditions, as well as in the sera and brains of patients with neurodegenerative diseases such as Parkinson's, Huntington's, Multiple Sclerosis, and Alzheimer's. Additionally, alterations in regional brain pH have been noted in these conditions. Acid-sensing ion channels (ASICs), including ASIC1a, activated by low pH levels, are highly abundant in the CNS and have recently been associated with various neurological disorders. Our study examined the impact of IL-6 on ASIC1a channels in cell cultures, demonstrating IL-6-induced the redistribution of cytosolic ASIC1a channels to the cell membrane. This redistribution was accompanied by increased ASIC1a current amplitude upon activation, as well as elevated levels of phosphorylated CaMKII and ERK kinases. Additionally, we observed posttranslational modifications on the ASIC1a channel itself. These findings provide insight into a potential link between inflammatory processes and neurodegenerative mechanisms, highlighting ASIC1a channels as promising therapeutic targets in these conditions.

Segmental Upregulation of ASIC1 Channels in the Formalin Acute Pain Mouse Model.

BACKGROUND: Hindpaw injection of formalin in rodents is used to assess acute persistent pain. The response to formalin is biphasic. The initial response (first minutes) is thought to be linked to inflammatory, peripheral mechanisms, while the latter (around 30 min after the injection), is linked to central mechanisms. This model is useful to analyze the effect of drugs at one or both phases, and the involvement of ion channels in the response. Acid-sensing ion channels (ASICs) regulate synaptic activities and play important roles in pain conditions. Recently, psalmotoxin-1 (Pctx-1), a toxin that inhibits ASIC1a-constituted channels, and antisense ASIC1a-RNA, intrathecal administered in mice were shown to affect both phases of the test. METHODS: The mouse formalin test was performed on C57/BL6 7- to 9-week-old mice. Behavioral tests were conducted and tissue was extracted to detect proteins (ASIC1 and pERK) and ASIC1-mRNA and mir485-5p levels. RESULTS: The injection of formalin was accompanied by an increase in ASIC1 levels. This was detected at the contralateral anterior cingulate cortex (ACC) compared to the ipsilateral side, and both sides of the ACC of vehicle-injected animals. At the spinal cord and dorsal root ganglia, ASIC1 levels followed a gradient stronger at lumbar (L) 3 and decreased towards L5. Gender differences were detected at the ACC; with female mice showing higher ASIC1a levels at the ACC. No significant changes in ASIC1-mRNA levels were detected. Evidence suggests ASIC1 upregulation depends on regulatory microRNAs. CONCLUSION: This work highlights the important role of ASIC1 in pain and the potential role of pharmacological therapies aimed at this channel.