{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T04:57:11Z","timestamp":1783573031101,"version":"3.55.0"},"reference-count":16,"publisher":"National Academy of Sciences","issue":"8","license":[{"start":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T00:00:00Z","timestamp":1613606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Australian National Health and Medical Reseach Council","award":["APP1067940"],"award-info":[{"award-number":["APP1067940"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2021,2,23]]},"abstract":"<jats:p>Acid-sensing ion channels (ASICs) are expressed in the nervous system, activated by acidosis, and implicated in pain pathways. Mambalgins are peptide inhibitors of ASIC1 and analgesic in rodents via inhibition of centrally expressed ASIC1a and peripheral ASIC1b. This activity has generated interest in mambalgins as potential therapeutics. However, most mechanism and structure\u2013activity relationship work on mambalgins has focused on ASIC1a, and neglected the peripheral analgesic target ASIC1b. Here, we compare mambalgin potency and mechanism of action at heterologously expressed rat and human ASIC1 variants. Unlike the nanomolar inhibition at ASIC1a and rodent ASIC1b, we find mambalgin-3 only weakly inhibits human ASIC1b and ASIC1b\/3 under severe acidosis, but potentiates currents under mild\/moderate acidosis. Our data highlight the importance of understanding the activity of potential ASIC-targeting pharmaceuticals at human channels.<\/jats:p>","DOI":"10.1073\/pnas.2021581118","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T15:56:23Z","timestamp":1613663783000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["Mambalgin-3 potentiates human acid-sensing ion channel 1b under mild to moderate acidosis: Implications as an analgesic lead"],"prefix":"10.1073","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0235-2029","authenticated-orcid":false,"given":"Ben","family":"Cristofori-Armstrong","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9788-2430","authenticated-orcid":false,"given":"Elena","family":"Budusan","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3616-0279","authenticated-orcid":false,"given":"Lachlan D.","family":"Rash","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/386173a0"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3529"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104030200"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.17.10240"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.171330"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11494"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.702373"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.01247"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000000397"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14462"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.57096"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.561076"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-018-0026-1"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200509303"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2019.03.004"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0215709"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.2021581118","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2021581118","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T06:31:48Z","timestamp":1649831508000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.2021581118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,19]]},"references-count":16,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2021,2,23]]}},"alternative-id":["10.1073\/pnas.2021581118"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2021581118","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,19]]},"assertion":[{"value":"2021-02-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2021581118"}}