Diversely evolved xibalbin variants from remipede venom inhibit potassium channels and activate PKA-II and Erk1/2 signaling.

Autor: Pinheiro-Junior EL; Toxicology and Pharmacology - Campus Gasthuisberg, University of Leuven (KU Leuven), Herestraat 49, PO Box 922, 3000, Louvain, Belgium., Alirahimi E; Department of Anesthesiology and Intensive Care Medicine, University Cologne, Translational Pain Research, University Hospital of Cologne, Cologne, Germany., Peigneur S; Toxicology and Pharmacology - Campus Gasthuisberg, University of Leuven (KU Leuven), Herestraat 49, PO Box 922, 3000, Louvain, Belgium., Isensee J; Department of Anesthesiology and Intensive Care Medicine, University Cologne, Translational Pain Research, University Hospital of Cologne, Cologne, Germany., Schiffmann S; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596, Frankfurt Am Main, Germany., Erkoc P; Institute of Pharmaceutical Biology, Goethe University Frankfurt, Max-Von-Laue-Str. 9, 60438, Frankfurt, Germany.; LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325, Frankfurt, Germany., Fürst R; Institute of Pharmaceutical Biology, Goethe University Frankfurt, Max-Von-Laue-Str. 9, 60438, Frankfurt, Germany.; LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325, Frankfurt, Germany., Vilcinskas A; LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325, Frankfurt, Germany.; Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology (IME-BR), Ohlebergsweg 14, 35394, Giessen, Germany., Sennoner T; Department of Informatics, Bioinformatics and Computational Biology, i12, Technical University of Munich, Boltzmannstr. 3, 85748, Garching, Munich, Germany., Koludarov I; Department of Informatics, Bioinformatics and Computational Biology, i12, Technical University of Munich, Boltzmannstr. 3, 85748, Garching, Munich, Germany., Hempel BF; Freie Unveristät Berlin, Veterinary Centre for Resistance Research (TZR), Robert-Von-Ostertag Str. 8, 14163, Berlin, Germany., Tytgat J; Toxicology and Pharmacology - Campus Gasthuisberg, University of Leuven (KU Leuven), Herestraat 49, PO Box 922, 3000, Louvain, Belgium., Hucho T; Department of Anesthesiology and Intensive Care Medicine, University Cologne, Translational Pain Research, University Hospital of Cologne, Cologne, Germany., von Reumont BM; LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Senckenberganlage 25, 60325, Frankfurt, Germany. bmvr@reumont.net.; Faculty of Biological Sciences, Institute of Cell Biology and Neuroscience, Goethe, Frankfurt, Max-Von-Laue-Str 13, 60438, Frankfurt, Germany. bmvr@reumont.net.
Jazyk: angličtina
Zdroj: BMC biology [BMC Biol] 2024 Jul 29; Vol. 22 (1), pp. 164. Date of Electronic Publication: 2024 Jul 29.
DOI: 10.1186/s12915-024-01955-5
Abstrakt: Background: 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.
Results: Our screenings revealed that all tested xibalbin variants particularly inhibit potassium channels. Xib 1 and xib 13 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 xib 1 and xib 13 increase PKA-II and Erk1/2 sensitization signaling in nociceptive neurons, which may initiate pain sensitization. Our phylogenetic analysis suggests that xib 13 either originates from the common ancestor of pancrustaceans or earlier while xib 1 is more restricted to remipedes. The ten-cysteine scaffolded xib 2 emerged from xib 1 , a result that is supported by our phylogenetic and machine learning-based analyses.
Conclusions: Our functional characterization of synthesized variants of xib 1 , xib 2 , and xib 13 elucidates their potential as inhibitors of potassium channels in mammalian systems. The specific interaction of xib 2 with Kv1.6 channels, which are relevant to treating variants of epilepsy, shows potential for further studies. At higher concentrations, xib 1 and xib 13 activate the kinases PKA-II and ERK1/2 in mammalian sensory neurons, suggesting pain sensitization and potential applications related to pain research and therapy. While tested insect channels suggest that all probably act as neurotoxins, the biological function of xib 1 , xib 2, and xib 13 requires further elucidation. A novel finding on their evolutionary origin is the apparent emergence of X. tulumensis-specific xib 2 from xib 1 . Our study is an important cornerstone for future studies to untangle the origin and function of these enigmatic proteins as important components of remipede but also other pancrustacean and arthropod venoms.
(© 2024. The Author(s).)
Databáze: MEDLINE
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