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Their venoms induce potentially deadly symptoms, including hyper- and hypotension, tachycardia, bradycardia and pulmonary oedema. Human envenomation is more frequent with the ground-dwelling species, including the infamous Sydney funnel-web spider (Atrax robustus); although, only two tree-dwelling species induce more severe envenomation. To unravel the mechanisms that lead to this stark difference in clinical outcomes, we investigated the venom transcriptome and proteome of arboreal Hadronyche cerberea and H. formidabilis. Overall, Hadronyche venoms comprised 44 toxin superfamilies, with 12 being exclusive to tree-dwellers. Surprisingly, the major venom components were neprilysins and uncharacterized peptides, in addition to the well-known \u03c9- and \u03b4-hexatoxins and double-knot peptides. The insecticidal effects of Hadronyche venom on sheep blowflies were more potent than Atrax venom, and the venom of both tree- and ground-dwelling species potently modulated human voltage-gated sodium channels, particularly NaV1.2. Only the venom of tree-dwellers exhibited potent modulation of voltage-gated calcium channels. H. formidabilis appeared to be under less diversifying selection pressure compared to the newly adapted tree-dweller, H. cerberea. Thus, this study contributes to unravelling the fascinating molecular and pharmacological basis for the severe envenomation caused by the Australian tree-dwelling funnel-web spiders.<\/jats:p>","DOI":"10.3390\/ijms232113077","type":"journal-article","created":{"date-parts":[[2022,10,30]],"date-time":"2022-10-30T04:57:34Z","timestamp":1667105854000},"page":"13077","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The Deadly Toxin Arsenal of the Tree-Dwelling Australian Funnel-Web Spiders"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0068-9974","authenticated-orcid":false,"given":"Fernanda C.","family":"Cardoso","sequence":"first","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia"},{"name":"Centre for Excellence in Innovation of Peptide and Protein Science, The University of Queensland, St Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandy S.","family":"Pineda","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia"},{"name":"Brain and Mind Centre, Faculty of Medicine and Health, School of Medical Sciences, The University of Sydney, Camperdown, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2514-3983","authenticated-orcid":false,"given":"Volker","family":"Herzig","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia"},{"name":"Centre for Bioinnovation, University of the Sunshine Coast, Sippy Downs, QLD 4556, Australia"},{"name":"School of Science, Technology and Engineering, University of the Sunshine Coast, Sippy Downs, QLD 4556, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0998-1581","authenticated-orcid":false,"given":"Kartik","family":"Sunagar","sequence":"additional","affiliation":[{"name":"Evolutionary Venomics Lab, Centre for Ecological Sciences, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9903-8484","authenticated-orcid":false,"given":"Naeem Yusuf","family":"Shaikh","sequence":"additional","affiliation":[{"name":"Evolutionary Venomics Lab, Centre for Ecological Sciences, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai-Hua","family":"Jin","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2308-2200","authenticated-orcid":false,"given":"Glenn F.","family":"King","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia"},{"name":"Centre for Excellence in Innovation of Peptide and Protein Science, The University of Queensland, St Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7454-6522","authenticated-orcid":false,"given":"Paul F.","family":"Alewood","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3470-923X","authenticated-orcid":false,"given":"Richard J.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2945-1484","authenticated-orcid":false,"given":"S\u00e9bastien","family":"Dutertre","sequence":"additional","affiliation":[{"name":"IBMM, Universit\u00e9 de Montpellier, CNRS, ENSCM, 34095 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"407","DOI":"10.5694\/j.1326-5377.2005.tb06760.x","article-title":"Funnel-web spider bite: A systematic review of recorded clinical cases","volume":"182","author":"Isbister","year":"2005","journal-title":"Med. 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