Upregulation of acid sensing ion channel 1a (ASIC1a) by hydrogen peroxide through the JNK pathway

Bao-ming Wu1, Jaree Bargaineer1, Ling Zhang1, Tao Yang1, Zhi-gang Xiong1, Tian-dong Leng1
1 epartment of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
Correspondence to: Zhi-gang Xiong:, Tian-dong Leng:,
DOI: 10.1038/s41401-020-00559-3
Received: 3 June 2020
Accepted: 18 October 2020
Advance online: 12 November 2020


Oxidative stress is intimately tied to neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis, and acute injuries, such as ischemic stroke and traumatic brain injury. Acid sensing ion channel 1a (ASIC1a), a proton-gated ion channel, has been shown to be involved in the pathogenesis of these diseases. However, whether oxidative stress affects the expression of ASIC1a remains elusive. In the current study, we examined the effect of hydrogen peroxide (H2O2), a major reactive oxygen species (ROS), on ASIC1a protein expression and channel function in NS20Y cells and primary cultured mouse cortical neurons. We found that treatment of the cells with H2O2 (20 μM) for 6 h or longer increased ASIC1a protein expression and ASIC currents without causing significant cell injury. H2O2 incubation activated mitogen-activated protein kinases (MAPKs) pathways, including the extracellular signal-regulated kinase1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 pathways. We found that neither inhibition of the MEK/ERK pathway by U0126 nor inhibition of the p38 pathway by SB203580 affected H2O2-induced ASIC1a expression, whereas inhibition of the JNK pathway by SP600125 potently decreased ASIC1a expression and abolished the H2O2- mediated increase in ASIC1a expression and ASIC currents. Furthermore, we found that H2O2 pretreatment increased the sensitivity of ASIC currents to the ASIC1a inhibitor PcTx1, providing additional evidence that H2O2 increases the expression of functional ASIC1a channels. Together, our data demonstrate that H2O2 increases ASIC1a expression/activation through the JNK signaling pathway, which may provide insight into the pathogenesis of neurological disorders that involve both ROS and activation of ASIC1a.
Keywords: acid-sensing ion channels (ASICs); hydrogen peroxide (H2O2); reactive oxygen species (ROS); mitogen-activated protein kinase (MAPK); c-Jun N-terminal kinase (JNK)

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