{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T01:27:20Z","timestamp":1773797240856,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T00:00:00Z","timestamp":1742860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sarah Morrison Research Award from the University of Missouri\u2014Kansas City School Medicine, Missouri, USA","award":["19AIREA34470007"],"award-info":[{"award-number":["19AIREA34470007"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["19AIREA34470007"],"award-info":[{"award-number":["19AIREA34470007"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cyanide (CN) is a potent, fast-acting toxicant that impacts endogenous biomolecules in the nervous system, including acid-sensing ion channels (ASICs), which play a vital role in various neurological and psychological conditions. Here, we demonstrate that CN rapidly potentiates ASIC currents in cultured mouse cortical neurons in a dose-dependent manner while causing a leftward shift in the pH dose\u2013response curve. Notably, this potentiation was unaffected by a 30-min CN treatment or the presence of ATP in the recording pipette. Further investigations into the role of zinc revealed that TPEN, a high-affinity zinc chelator, did not enhance ASIC currents following CN pretreatment, nor did CN influence the potentiation of ASIC currents induced by TPEN. Low-affinity zinc blocked the potentiation of ASIC currents by CN. CN potentiated ASIC currents in cortical neurons from ASIC2 but not from ASIC1a knockout mice. In experiments with CHO cells expressing homomeric ASIC1a and heteromeric ASIC1a\/2, CN potentiated ASIC1a currents but had no effect on homomeric ASIC1b, ASIC2a, or ASIC3 channels. Mutating lysine 133 (K133) to arginine (R) in the extracellular domain of ASIC1a abolished CN\u2019s effect, suggesting that CN potentiates ASIC1a currents primarily via high-affinity zinc binding, with K133 being critical for this modulation.<\/jats:p>","DOI":"10.3390\/biom15040479","type":"journal-article","created":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T10:48:58Z","timestamp":1742899738000},"page":"479","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ASIC1a-Dependent Potentiation of Acid-Sensing Ion Channel Currents by Cyanide"],"prefix":"10.3390","volume":"15","author":[{"given":"Qian","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6783-2827","authenticated-orcid":false,"given":"Felix","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amber","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuyang","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Detroit Medical Center, School of Medicine, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Cascone","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dylan","family":"Glaser","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6781-0468","authenticated-orcid":false,"given":"Xiang-Ping","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/386173a0","article-title":"A proton-gated cation channel involved in acid-sensing","volume":"386","author":"Waldmann","year":"1997","journal-title":"Nature"},{"key":"ref_2","first-page":"1570","article-title":"Acid-Sensing Ion Channels: Focus on Physiological and Some Pathological Roles in the Brain","volume":"19","author":"Storozhuk","year":"2021","journal-title":"Curr. Neuropharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1113\/EP090762","article-title":"Genetic exploration of roles of acid-sensing ion channel subtypes in neurosensory mechanotransduction including proprioception","volume":"109","author":"Lin","year":"2024","journal-title":"Exp. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1038\/nn.3750","article-title":"Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity","volume":"17","author":"Kreple","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.neuropharm.2014.12.010","article-title":"Two aspects of ASIC function: Synaptic plasticity and neuronal injury","volume":"94","author":"Huang","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.cell.2004.08.026","article-title":"Neuroprotection in ischemia: Blocking calcium-permeable acid-sensing ion channels","volume":"118","author":"Xiong","year":"2004","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/s41586-024-07684-7","article-title":"Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury","volume":"631","author":"Lai","year":"2024","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Yin, T., Lindley, T.E., Albert, G.W., Ahmed, R., Schmeiser, P.B., Grady, M.S., Howard, M.A., and Welsh, M.J. (2013). Loss of Acid sensing ion channel-1a and bicarbonate administration attenuate the severity of traumatic brain injury. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072379"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1089\/neu.2020.7568","article-title":"Acid-Ion Sensing Channel 1a Deletion Reduces Chronic Brain Damage and Neurological Deficits after Experimental Traumatic Brain Injury","volume":"38","author":"Cheng","year":"2021","journal-title":"J. Neurotrauma"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1006\/nbdi.2000.0331","article-title":"Regional and subunit-specific downregulation of acid-sensing ion channels in the pilocarpine model of epilepsy","volume":"8","author":"Biagini","year":"2001","journal-title":"Neurobiol. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e14596","DOI":"10.1111\/cns.14596","article-title":"Inhibiting acid-sensing ion channel exerts neuroprotective effects in experimental epilepsy via suppressing ferroptosis","volume":"30","author":"Shi","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2478","DOI":"10.1111\/bph.14990","article-title":"Acid-sensing ion channel 3 blockade inhibits durovascular and nitric oxide-mediated trigeminal pain","volume":"177","author":"Holton","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Chang, C.T., Fong, S.W., Lee, C.H., Chuang, Y.C., Lin, S.H., and Chen, C.C. (2019). Involvement of Acid-Sensing Ion Channel 1b in the Development of Acid-Induced Chronic Muscle Pain. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.01247"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.neuroscience.2013.04.059","article-title":"Differential regulation of locomotor activity to acute and chronic cocaine administration by acid-sensing ion channel 1a and 2 in adult mice","volume":"246","author":"Jiang","year":"2013","journal-title":"Neuroscience"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.coph.2007.09.001","article-title":"Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases","volume":"8","author":"Xiong","year":"2008","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/0041-008X(86)90251-6","article-title":"Cyanide-induced neurotoxicity: Role of neuronal calcium","volume":"84","author":"Johnson","year":"1986","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Lachowicz, J.I., Alexander, J., and Aaseth, J.O. (2024). Cyanide and Cyanogenic Compounds-Toxicity, Molecular Targets, and Therapeutic Agents. Biomolecules, 14.","DOI":"10.3390\/biom14111420"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1006\/taap.1999.8630","article-title":"Differential susceptibility of brain areas to cyanide involves different modes of cell death","volume":"156","author":"Mills","year":"1999","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1124\/jpet.102.039453","article-title":"Cyanide induces different modes of death in cortical and mesencephalon cells","volume":"303","author":"Prabhakaran","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_20","first-page":"35","article-title":"N-methyl-D-aspartate receptors mediate cyanide-induced cytotoxicity in hippocampal cultures","volume":"14","author":"Patel","year":"1993","journal-title":"Neurotoxicology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/(SICI)1099-0461(1999)13:5<253::AID-JBT5>3.0.CO;2-Z","article-title":"Cyanide interaction with redox modulatory sites enhances NMDA receptor responses","volume":"13","author":"Sun","year":"1999","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2877","DOI":"10.1152\/physrev.00034.2022","article-title":"Synaptic memory and CaMKII","volume":"103","author":"Nicoll","year":"2023","journal-title":"Physiol. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"109019","DOI":"10.1016\/j.neuropharm.2022.109019","article-title":"Ion flux-independent NMDA receptor signaling","volume":"210","author":"Park","year":"2022","journal-title":"Neuropharmacology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1016\/S0022-3565(24)36517-6","article-title":"Modulation of the NMDA receptor by cyanide: Enhancement of receptor-mediated responses","volume":"280","author":"Sun","year":"1997","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0006-3495(01)75684-6","article-title":"High-affinity Zn block in recombinant N-methyl-D-aspartate receptors with cysteine substitutions at the Q\/R\/N site","volume":"81","author":"Amar","year":"2001","journal-title":"Biophys. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5711","DOI":"10.1523\/JNEUROSCI.17-15-05711.1997","article-title":"High-affinity zinc inhibition of NMDA NR1-NR2A receptors","volume":"17","author":"Paoletti","year":"1997","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/634","article-title":"Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition","volume":"1","author":"Zheng","year":"1998","journal-title":"Nat. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8678","DOI":"10.1523\/JNEUROSCI.2844-04.2004","article-title":"Subunit-Dependent High-Affinity Zinc Inhibition of Acid-Sensing Ion Channels","volume":"24","author":"Chu","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5329","DOI":"10.1523\/JNEUROSCI.0938-06.2006","article-title":"ASIC1a-specific modulation of acid-sensing ion channels in mouse cortical neurons by redox reagents","volume":"26","author":"Chu","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Jiang, Q., Peterson, A.M., Chu, Y., Yao, X., Zha, X.M., and Chu, X.P. (2020). Histidine Residues Are Responsible for Bidirectional Effects of Zinc on Acid-Sensing Ion Channel 1a\/3 Heteromeric Channels. Biomolecules, 10.","DOI":"10.3390\/biom10091264"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.neuroscience.2009.04.029","article-title":"Characterization of acid-sensing ion channels in medium spiny neurons of mouse striatum","volume":"162","author":"Jiang","year":"2009","journal-title":"Neuroscience"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Baksheeva, V.E., Roman, A.Y., Villard, C., Devred, F., Byrne, D., Yatoui, D., Zalevsky, A.O., Vologzhannikova, A.A., Sokolov, A.S., and Permyakov, S.E. (2021). Mechanism of Zn2+ and Ca2+ Binding to Human S100A1. Biomolecules, 11.","DOI":"10.3390\/biom11121823"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Baksheeva, V.E., Tsvetkov, P.O., Zalevsky, A.O., Vladimirov, V.I., Gorokhovets, N.V., Zinchenko, D.V., Permyakov, S.E., Devred, F., and Zernii, E.Y. (2022). Zinc Modulation of Neuronal Calcium Sensor Proteins: Three Modes of Interaction with Different Structural Outcomes. Biomolecules, 12.","DOI":"10.3390\/biom12070956"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e202012585","DOI":"10.1085\/jgp.202012585","article-title":"Zn2+-induced changes in Cav2.3 channel function: An electrophysiological and modeling study","volume":"152","author":"Neumaier","year":"2020","journal-title":"J. Gen. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wang, B., Fang, T., and Chen, H. (2023). Zinc and Central Nervous System Disorders. Nutrients, 15.","DOI":"10.3390\/nu15092140"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Tyczy\u0144ska, M., G\u0119dek, M., Brachet, A., Str\u0119k, W., Flieger, J., Teresi\u0144ski, G., and Baj, J. (2024). Trace Elements in Alzheimer\u2019s Disease and Dementia: The Current State of Knowledge. J. Clin. Med., 13.","DOI":"10.3390\/jcm13082381"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/4\/479\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:59:35Z","timestamp":1760029175000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/4\/479"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,25]]},"references-count":36,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["biom15040479"],"URL":"https:\/\/doi.org\/10.3390\/biom15040479","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,25]]}}}