Protein Kinase C Regulates ASIC1a Protein Expression and Channel Function via NF-kB Signaling Pathway
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Protein Kinase C Regulates ASIC1a Protein Expression and Channel Function via NF-kB Signaling Pathway Ling Zhang 1,2 & Tian-Dong Leng 2 & Tao Yang 2 & Jun Li 1 & Zhi-Gang Xiong 2 Received: 28 January 2020 / Accepted: 3 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Tissue acidosis is a common feature in many pathological conditions. Activation of acid-sensing ion channel 1a (ASIC1a) plays a key role in acidosis-mediated neurotoxicity. Protein kinase C (PKC) activity has been proved to be associated with many physiological processes and pathological conditions; however, whether PKC activation regulates ASIC1a protein expression and channel function remains ill defined. In this study, we demonstrated that treatment with phorbol 12-myristate 13-acetate (PMA, a PKC activator) for 6 h significantly increased ASIC1a protein expression and ASIC currents in NS20Y cells, a neuronal cell line, and in primary cultured mouse cortical neurons. In contrast, treatment with Calphostin C (a nonselective PKC inhibitor) for 6 h or longer decreased ASIC1a protein expression and ASIC currents. Similar to Calphostin C, PKC α and βI inhibitor Go6976 exposure also reduced ASIC1a protein expression. The reduction in ASIC1a protein expression by PKC inhibition involves a change in ASIC1a protein degradation, which is mediated by ubiquitin-proteasome system (UPS)-dependent degradation pathway. In addition, we showed that PKC regulation of ASIC1a protein expression involves NF-κB signaling pathway. Consistent with their effects on ASIC1a protein expression and channel function, PKC inhibition protected NS20Y cells against acidosis-induced cytotoxicity, while PKC activation potentiated acidosis-induced cells injury. Together, these results indicate that ASIC1a protein expression and channel function are closely regulated by the activity of protein kinase C and its downstream signaling pathway(s). Keywords ASIC1a . Protein kinase C . Protein expression . Protein degradation . NF-κB
Introduction Tissue acidosis is a common feature in many pathological conditions such as inflammation, ischemic stroke, infections, and cancer [1–4]. In brain ischemia, for example, pH can easily drop from 7.4 to 6.5 or lower [5–7], which can activate a novel proton sensor, the acid-sensing ion channels (ASICs), Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02056-4) contains supplementary material, which is available to authorized users. * Zhi-Gang Xiong [email protected] Jun Li [email protected] 1
School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, China
2
Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, Atlanta, GA 30310, USA
members of degenerin/epithelial sodium channel superfamily (DEG/ENaC) [8, 9]. These channels are highly expressed in peripheral sensory and central neurons and play a critical role in the perception of a wide range of pH changes in conditions related to tissue aci
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