biostudies-literaturePinheiro-Junior ELSão Paulo Research FoundationF.W.O.-VlaanderenJohann Wolfgang Goethe-Universität, Frankfurt am MainLOEWE TBGEU COST ActionKU Leuven funding164https://www.ebi.ac.uk/biostudies/studies/S-EPMC11288129biostudies-literatureUnknown22(1)<h4>Background</h4>The identification of novel toxins from overlooked and taxonomically exceptional species bears potential for various pharmacological applications. The remipede Xibalbanus tulumensis, an underwater cave-dwelling crustacean, is the only crustacean for which a venom system has been described. Its venom contains several xibalbin peptides that have an inhibitor cysteine knot (ICK) scaffold.<h4>Results</h4>Our screenings revealed that all tested xibalbin variants particularly inhibit potassium channels. Xib₁ and xib₁₃ with their eight-cysteine domain similar to spider knottins also inhibit voltage-gated sodium channels. No activity was noted on calcium channels. Expanding the functional testing, we demonstrate that xib₁ and xib₁₃ incBMC biologyDiversely evolved xibalbin variants from remipede venom inhibit potassium channels and activate PKA-II and Erk1/2 signaling.PMC11288129G0E7120NGOC2319 NCA19144 EUVENGOA4919 N2016/04761-4PDM/19/164Furst RHempel BFKoludarov IErkoc PPeigneur SIsensee JTytgat Jvon Reumont BMSchiffmann SSennoner THucho TAlirahimi EPinheiro-Junior ELVilcinskas AfalseDiversely evolved xibalbin variants from remipede venom inhibit potassium channels and activate PKA-II and Erk1/2 signaling.<h4>Background</h4>The identification of novel toxins from overlooked and taxonomically exceptional species bears potential for various pharmacological applications. The remipede Xibalbanus tulumensis, an underwater cave-dwelling crustacean, is the only crustacean for which a venom system has been described. Its venom contains several xibalbin peptides that have an inhibitor cysteine knot (ICK) scaffold.<h4>Results</h4>Our screenings revealed that all tested xibalbin variants particularly inhibit potassium channels. Xib₁ and xib₁₃ with their eight-cysteine domain similar to spider knottins also inhibit voltage-gated sodium channels. No activity was noted on calcium channels. Expanding the functional testing, we demonstrate that xib₁ and xib₁₃ inc2024-01-01T00:00:00Z2024 Jul2026-06-03T00:18:27.999Z2026-04-22T03:11:59.952ZS-EPMC112881293907555810.1186/s12915-024-01955-5