{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T23:07:56Z","timestamp":1781478476223,"version":"3.54.1"},"reference-count":88,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000923","name":"Australian Research Council Discovery Project","doi-asserted-by":"publisher","award":["DP210102406"],"award-info":[{"award-number":["DP210102406"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000923","name":"Australian Research Council Discovery Project","doi-asserted-by":"publisher","award":["DP200102880"],"award-info":[{"award-number":["DP200102880"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Many vertebrates have evolved resistance to snake venom as a result of coevolutionary chemical arms races. In Australian skinks (family Scincidae), who often encounter venomous elapid snakes, the frequency, diversity, and molecular basis of venom resistance have been unexplored. This study investigated the evolution of neurotoxin resistance in Australian skinks, focusing on mutations in the muscle nicotinic acetylcholine receptor (nAChR) \u03b11 subunit\u2019s orthosteric site that prevent pathophysiological binding by \u03b1-neurotoxins. We sampled a broad taxonomic range of Australian skinks and sequenced the nAChR \u03b11 subunit gene. Key resistance-conferring mutations at the toxin-binding site (N-glycosylation motifs, proline substitutions, arginine insertions, changes in the electrochemical state of the receptor, and novel cysteines) were identified and mapped onto the skink organismal phylogeny. Comparisons with other venom-resistant taxa (amphibians, mammals, and reptiles) were performed, and structural modelling and binding assays were used to evaluate the impact of these mutations. Multiple independent origins of \u03b1-neurotoxin resistance were found across diverse skink lineages. Thirteen lineages evolved at least one resistance motif and twelve additional motifs evolved within these lineages, for a total of twenty-five times of \u03b1-neurotoxic venoms resistance. These changes sterically or electrostatically inhibit neurotoxin binding. Convergent mutations at the orthosteric site include the introduction of N-linked glycosylation sites previously known from animals as diverse as cobras and mongooses. However, an arginine (R) substitution at position 187 was also shown to have evolved on multiple occasions in Australian skinks, a modification previously shown to be responsible for the Honey Badger\u2019s iconic resistance to cobra venom. Functional testing confirmed this mode of resistance in skinks. Our findings reveal that venom resistance has evolved extensively and convergently in Australian skinks through repeated molecular adaptations of the nAChR in response to the enormous selection pressure exerted by elapid snakes subsequent to their arrival and continent-wide dispersal in Australia. These toxicological findings highlight a remarkable example of convergent evolution across vertebrates and provide insight into the adaptive significance of toxin resistance in snake\u2013lizard ecological interactions.<\/jats:p>","DOI":"10.3390\/ijms26157510","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T07:45:11Z","timestamp":1754466311000},"page":"7510","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Make Acetylcholine Great Again! Australian Skinks Evolved Multiple Neurotoxin-Proof Nicotinic Acetylcholine Receptors in Defiance of Snake Venom"],"prefix":"10.3390","volume":"26","author":[{"given":"Uthpala","family":"Chandrasekara","sequence":"first","affiliation":[{"name":"Adaptive Biotoxicology Lab, School of the Environment, University of Queensland, St Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2230-8183","authenticated-orcid":false,"given":"Marco","family":"Mancuso","sequence":"additional","affiliation":[{"name":"Adaptive Biotoxicology Lab, School of the Environment, University of Queensland, St Lucia, QLD 4072, Australia"},{"name":"Department of Biological, Geological and Environmental Sciences, University of Catania, Via Etnea, 64, 95131 Catania, CT, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenn","family":"Shea","sequence":"additional","affiliation":[{"name":"Sydney School of Veterinary Science, B01, University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Australian Museum Research Institute, The Australian Museum, Sydney, NSW 2010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Jones","sequence":"additional","affiliation":[{"name":"Adaptive Biotoxicology Lab, School of the Environment, University of Queensland, St Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6900-8241","authenticated-orcid":false,"given":"Jacek","family":"Kwiatkowski","sequence":"additional","affiliation":[{"name":"Queensland Emory Drug Discovery Initiative, Uniquest, University of Queensland, St Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dane","family":"Trembath","sequence":"additional","affiliation":[{"name":"Australian Museum Research Institute, The Australian Museum, Sydney, NSW 2010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhinandan","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"Adaptive Biotoxicology Lab, School of the Environment, University of Queensland, St Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6665-3395","authenticated-orcid":false,"given":"Terry","family":"Bertozzi","sequence":"additional","affiliation":[{"name":"South Australian Museum, North Terrace, Adelaide, SA 5000, Australia"},{"name":"School of Biological Sciences, The University of Adelaide, Adelaide, SA 5001, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8629-354X","authenticated-orcid":false,"given":"Michael G.","family":"Gardner","sequence":"additional","affiliation":[{"name":"College of Science and Engineering, Flinders University, GPO Box 2100, Adelaide, SA 5001, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conrad J.","family":"Hoskin","sequence":"additional","affiliation":[{"name":"College of Science & Engineering, James Cook University, Townsville, QLD 4811, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0385-500X","authenticated-orcid":false,"given":"Christina N.","family":"Zdenek","sequence":"additional","affiliation":[{"name":"Australian Reptile Academy, Ripley, QLD 4306, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6661-1283","authenticated-orcid":false,"given":"Bryan G.","family":"Fry","sequence":"additional","affiliation":[{"name":"Adaptive Biotoxicology Lab, School of the Environment, University of Queensland, St Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1146\/annurev.genom.9.081307.164356","article-title":"The toxicogenomic multiverse: Convergent recruitment of proteins into animal venoms","volume":"10","author":"Fry","year":"2009","journal-title":"Annu. 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