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

Acta Pharmacologica Sinica volume 42, pages 1248–1255 (2021)Cite this article

Abstract

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.

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Fig. 1: Effect of H2O2 on cell injury and ASIC1a protein expression in NS20Y cells.
Fig. 2: Effect of H2O2 on ASIC currents in NS20Y cells.
Fig. 3: Effect of H2O2 on the activation of MAPK signaling pathways in NS20Y cells.
Fig. 4: Effect of MAPK signaling pathway blockade on the H2O2-mediated increase in ASIC1a expression.
Fig. 5: Effect of JNK pathway blockade on H2O2-mediated changes in ASIC currents.
Fig. 6: H2O2 increases ASIC1a protein expression and ASIC currents in primary cultured mouse cortical neurons.
Fig. 7: H2O2 increases the sensitivity of ASIC currents to the inhibitory effect of PcTx1 in primary cultured mouse cortical neurons.

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Acknowledgements

ASIC1a antibody was a gift from Dr. Xiang-ming Zha (University of South Alabama, USA). This study was supported by National Institutes of Health (NIH) Grants SC3GM122593 (tl) and National Center for Minority Health and Health Disparities of the National Institutes of Health (U54MD007602).

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Affiliations

  1. Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, 30310, USA

    Bao-ming Wu, Jaree Bargaineer, Ling Zhang, Tao Yang, Zhi-gang Xiong & Tian-dong Leng

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  1. Bao-ming Wu
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Contributions

BMW performed the electrophysiology experiments. JB and LZ performed the Western blot experiments. TY performed the neuronal culture. ZGX and TDL designed the experiment, interpreted the data and wrote the paper.

Corresponding authors

Correspondence to Zhi-gang Xiong or Tian-dong Leng.

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Wu, Bm., Bargaineer, J., Zhang, L. et al. Upregulation of acid sensing ion channel 1a (ASIC1a) by hydrogen peroxide through the JNK pathway. Acta Pharmacol Sin 42, 1248–1255 (2021). https://doi.org/10.1038/s41401-020-00559-3

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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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