Region specific contribution of ASIC2 to acidosis-and ischemia-induced neuronal injury

Jiang, Nan; Wu, Jiansheng; Leng, Tiandong; Yang, Tao; Zhou, Yangjie; Jiang, Qian; Wang, Bin; Hu, Youjia; Ji, Yonghua; Simon, Roger P.; Chu, Xiang‐Ping; Xiong, Zhi‐Gang; Zha, Xiang-ming

doi:10.1177/0271678x16630558

Cited by 29 publications

(67 citation statements)

References 54 publications

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“…Recently, it has been reported that ASIC2a enhances the surface expression of ASIC1a (22, 23). To test whether ASIC2a can also deliver ASIC3 to the cell surface, we co-expressed ASIC2a and ASIC3 in HEK293T cells.…”

Section: Resultsmentioning

confidence: 99%

ASIC2a-dependent increase of ASIC3 surface expression enhances the sustained component of the currents

et al. 2016

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Acid-sensing ion channels (ASICs) are proton-gated cation channels widely expressed in the nervous system. Proton sensing by ASICs has been known to mediate pain, mechanosensation, taste transduction, learning and memory, and fear. In this study, we investigated the differential subcellular localization of ASIC2a and ASIC3 in heterologous expression systems. While ASIC2a targeted the cell surface itself, ASIC3 was mostly accumulated in the ER with partial expression in the plasma membrane. However, when ASIC3 was co-expressed with ASIC2a, its surface expression was markedly increased. By using bimolecular fluorescence complementation (BiFC) assay, we confirmed the heteromeric association between ASIC2a and ASIC3 subunits. In addition, we observed that the ASIC2a-dependent surface trafficking of ASIC3 remarkably enhanced the sustained component of the currents. Our study demonstrates that ASIC2a can increase the membrane conductance sensitivity to protons by facilitating the surface expression of ASIC3 through herteromeric assembly. [BMB Reports 2016; 49(10): 542-547]

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Section: Resultsmentioning

confidence: 99%

ASIC2a-dependent increase of ASIC3 surface expression enhances the sustained component of the currents

et al. 2016

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“…All constructs were verified by sequencing. ASIC antibodies used the following: a rabbit anti-ASIC1 antibody (14) and a goat anti-ASIC1 (SC-13905; Santa Cruz, Biotechnology, Dallas, TX, USA) and rabbit anti-ASIC2 (21). Antibody specificity was verified by the lack of signals in corresponding ASIC knockout mice (14,21).…”

Section: Constructs and Reagentsmentioning

confidence: 99%

“…ASIC antibodies used the following: a rabbit anti-ASIC1 antibody (14) and a goat anti-ASIC1 (SC-13905; Santa Cruz, Biotechnology, Dallas, TX, USA) and rabbit anti-ASIC2 (21). Antibody specificity was verified by the lack of signals in corresponding ASIC knockout mice (14,21). Other antibodies used were the following: mouse anti-N-cadherin (MA1-159; Thermo Fisher Scientific, Waltham, MA, USA); Alexa 488-, 568-, 680-, and 800-conjugated secondary antibodies (Thermo Fisher Scientific and Li-Cor Biosciences, Lincoln, NE, USA); and Dylight 488-, 680-, and 800-conjugated secondary antibodies (Thermo Fisher Scientific).…”

Section: Constructs and Reagentsmentioning

confidence: 99%

“…Human and mouse cortical tissues were blotted for ASIC1 and ASIC2, which recognize both ASIC2a and -2b. Antibody specificity was verified using the corresponding ASIC knockouts (14,21). Human and mouse tissues were not statistically different in the relative ratio of ASIC1a:ASIC2a (P .…”

Section: Deglycosylationmentioning

confidence: 99%

“…ASIC1a null mice have altered behavioral outcome in multiple fear-and anxiety-related tests (10)(11)(12). In addition, in acidotic conditions in vitro, as well as in rodent models of ischemia, multiple sclerosis, and traumatic brain injury, the deletion of ASIC1a or ASIC2 has a protective effect (13)(14)(15)(16)(17). These data demonstrate that ASICs, especially ASIC1a, are important mediators of acid signaling in the brain and a promising therapeutic target to alleviate acidosis-related neuronal injuries.…”

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Human ASIC1a mediates stronger acid‐induced responses as compared with mouse ASICIa

Jiang

et al. 2018

FASEB j.

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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.

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Functional characterization of acid-sensing ion channels in the cerebellum-originating medulloblastoma cell line DAOY and in cerebellar granule neurons

Pissas

Schilling

Tian

et al. 2023

Pflugers Arch - Eur J Physiol

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Acid-sensing ion channels (ASICs) are Na+ channels that are almost ubiquitously expressed in neurons of the brain. Functional ASIC1a is also expressed in glioblastoma stem cells, where it might sense the acidic tumor microenvironment. Prolonged acidosis induces cell death in neurons and reduces tumor sphere formation in glioblastoma via activation of ASIC1a. It is currently unknown whether ASICs are expressed and involved in acid-induced cell death in other types of brain tumors. In this study, we investigated ASICs in medulloblastoma, using two established cell lines, DAOY and UW228, as in vitro models. In addition, we characterized ASICs in the most numerous neuron of the brain, the cerebellar granule cell, which shares the progenitor cell with some forms of medulloblastoma. We report compelling evidence using RT-qPCR, western blot and whole-cell patch clamp that DAOY and cerebellar granule cells, but not UW228 cells, functionally express homomeric ASIC1a. Additionally, Ca2+-imaging revealed that extracellular acidification elevated intracellular Ca2+-levels in DAOY cells independently of ASICs. Finally, we show that overexpression of RIPK3, a key component of the necroptosis pathway, renders DAOY cells susceptible to acid-induced cell death via activation of ASIC1a. Our data support the idea that ASIC1a is an important acid sensor in brain tumors and that its activation has potential to induce cell death in tumor cells.

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Region specific contribution of ASIC2 to acidosis-and ischemia-induced neuronal injury

Cited by 29 publications

References 54 publications

ASIC2a-dependent increase of ASIC3 surface expression enhances the sustained component of the currents

ASIC2a-dependent increase of ASIC3 surface expression enhances the sustained component of the currents

Human ASIC1a mediates stronger acid‐induced responses as compared with mouse ASICIa

Functional characterization of acid-sensing ion channels in the cerebellum-originating medulloblastoma cell line DAOY and in cerebellar granule neurons

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