{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:44:16Z","timestamp":1787312656651,"version":"build-2736575974"},"reference-count":56,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T00:00:00Z","timestamp":1678406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01NS128018"],"award-info":[{"award-number":["R01NS128018"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["GM122593"],"award-info":[{"award-number":["GM122593"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"SC3","doi-asserted-by":"publisher","award":["R01NS128018"],"award-info":[{"award-number":["R01NS128018"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"SC3","doi-asserted-by":"publisher","award":["GM122593"],"award-info":[{"award-number":["GM122593"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>KB-R7943, an isothiourea derivative, is widely used as a pharmacological inhibitor of reverse sodium\u2013calcium exchanger (NCX). It has been shown to have neuroprotective and analgesic effects in animal models; however, the detailed molecular mechanisms remain elusive. In the current study, we investigated whether KB-R7943 modulates acid-sensing ion channels (ASICs), a group of proton-gated cation channels implicated in the pathophysiology of various neurological disorders, using the whole-cell patch clamp techniques. Our data show that KB-R7943 irreversibly inhibits homomeric ASIC1a channels heterologously expressed in Chinese Hamster Ovary (CHO) cells in a use- and concentration-dependent manner. It also reversibly inhibits homomeric ASIC2a and ASIC3 channels in CHO cells. Both the transient and sustained current components of ASIC3 are inhibited. Furthermore, KB-R7943 inhibits ASICs in primary cultured peripheral and central neurons. It inhibits the ASIC-like currents in mouse dorsal root ganglion (DRG) neurons and the ASIC1a-like currents in mouse cortical neurons. The inhibition of the ASIC1a-like current is use-dependent and unrelated to its effect on NCX since neither of the other two well-characterized NCX inhibitors, including SEA0400 and SN-6, shows an effect on ASIC. Our data also suggest that the isothiourea group, which is lacking in other structurally related analogs that do not affect ASIC1a-like current, may serve as a critical functional group. In summary, we characterize KB-R7943 as a new ASIC inhibitor. It provides a novel pharmacological tool for the investigation of the functions of ASICs and could serve as a lead compound for developing small-molecule drugs for treating ASIC-related disorders.<\/jats:p>","DOI":"10.3390\/biom13030507","type":"journal-article","created":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T02:30:33Z","timestamp":1678415433000},"page":"507","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Inhibition of Acid-Sensing Ion Channels by KB-R7943, a Reverse Na+\/Ca2+ Exchanger Inhibitor"],"prefix":"10.3390","volume":"13","author":[{"given":"Hua-Wei","family":"Sun","sequence":"first","affiliation":[{"name":"Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6781-0468","authenticated-orcid":false,"given":"Xiang-Ping","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger P.","family":"Simon","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2824-4168","authenticated-orcid":false,"given":"Zhi-Gang","family":"Xiong","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Dong","family":"Leng","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,10]]},"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","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/S0959-4388(98)80070-6","article-title":"H(+)-gated cation channels: Neuronal acid sensors in the NaC\/DEG family of ion channels","volume":"8","author":"Waldmann","year":"1998","journal-title":"Curr. 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