| 6 | Upregulation of acid sensing ion channel 1a (ASIC1a) by hydrogen peroxide through the JNK pathway显示文摘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(H_(2)O_(2)),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 H_(2)O_(2)(20μM)for 6 h or longer increased ASIC1a protein expression and ASIC currents without causing significant cell injury.H_(2)O_(2) 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 H_(2)O_(2)-induced ASIC1a expression,whereas inhibition of the JNK pathway by SP600125 potently decreased ASIC1a expression and abolished the H_(2)O_(2)-mediated increase in ASIC1a expression and ASIC currents.Furthermore,we found that H_(2)O_(2) pretreatment increased the sensitivity of ASIC currents to the ASIC1a inhibitor PcTx1,providing additional evidence that H_(2)O_(2) increases the expression of functional ASIC1a channels.Together,our data demonstrate that H_(2)O_(2) 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. | Bao-ming Wu Jaree Bargaineer Ling Zhang Tao Yang Zhi-gang Xiong Tian-dong Leng | 2021 | Acta Pharmacologica Sinica2021，42，8： | 0 |
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