Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
FASEB J. 2018 Jul;32(7):3832-3843. doi: 10.1096/fj.201701367R. Epub 2018 Feb 15.
Acid-sensing ion channels (ASICs) are the major proton receptor in the brain and a key mediator of acidosis-induced neuronal injuries in disease. Most of published data on ASIC function came from studies performed in mice, and relatively little is known about potential differences between human and mouse ASICs (hASIC and mASIC, respectively). This information is critical for us to better interpret the functional importance of ASICs in human disease. Here, we examined the expression of ASICs in acutely resected human cortical tissue. Compared with mouse cortex, human cortical tissue showed a similar ratio of ASIC1a:ASIC2a expression, had reduced ASIC2b level, and exhibited a higher membrane:total ratio of ASIC1a. We further investigated the mechanism for higher surface trafficking of hASIC1a in heterologous cells. A single amino acid at position 285 was critical for increased N-glycosylation and surface expression of hASIC1a. Consistent with the changes in trafficking and current, cells expressing hASIC1a or mASIC1a S285P mutant had a higher acid-activated calcium increase and exhibited worsened acidotoxicity. These data suggest that ASICs are likely to have a larger impact on acidosis-induced neuronal injuries in humans than mice, and this effect is, at least in part, a result of more efficient trafficking of hASIC1a.-Xu, Y., Jiang, Y.-Q., Li, C., He, M., Rusyniak, W. G., Annamdevula, N., Ochoa, J., Leavesley, S. J., Xu, J., Rich, T. C., Lin, M. T., Zha, X.-M. Human ASIC1a mediates stronger acid-induced responses as compared with mouse ASIC1a.
酸敏离子通道 (ASICs) 是大脑中的主要质子受体，也是疾病中酸中毒诱导神经元损伤的关键介质。大多数关于 ASIC 功能的已发表数据来自于在小鼠中进行的研究，而对于人类和小鼠 ASIC 之间（分别为 hASIC 和 mASIC）的潜在差异知之甚少。这些信息对于我们更好地解释 ASIC 在人类疾病中的功能重要性至关重要。在这里，我们检查了急性切除的人类皮质组织中 ASIC 的表达。与小鼠皮质相比，人类皮质组织表现出相似的 ASIC1a:ASIC2a 表达比例，ASIC2b 水平降低，并且 ASIC1a 的膜：总比例更高。我们进一步研究了 hASIC1a 在异源细胞中更高表面转运的机制。位置 285 处的单个氨基酸对于增加 hASIC1a 的 N-糖基化和表面表达至关重要。与转运和电流变化一致，表达 hASIC1a 或 mASIC1a S285P 突变体的细胞具有更高的酸激活钙增加，并表现出更严重的酸中毒毒性。这些数据表明，ASICs 可能对人类酸中毒诱导的神经元损伤的影响比小鼠更大，而这种影响至少部分是由于 hASIC1a 的转运效率更高。-许，Y.，江，Y.-Q.，李，C.，何，M.， Rusyniak，W. G.，Annamdevula，N.，Ochoa，J.，Leavesley，S. J.，许，J.，Rich，T. C.，Lin，M. T.，Zha，X.-M.人类 ASIC1a 介导的酸诱导反应强于小鼠 ASIC1a。
