Saggiomo Silvia Luiza, Peigneur Steve, Tytgat Jan, Daly Norelle L, Wilson David Thomas
Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
Toxicology and Pharmacology, Katholieke Universiteit (KU) Leuven, Belgium.
FEBS Open Bio. 2025 Mar;15(3):399-414. doi: 10.1002/2211-5463.13926. Epub 2024 Nov 20.
The stonefish Synanceia verrucosa and Synanceia horrida are arguably the most venomous fish species on earth and the culprits of severe stings in humans globally. Investigation into the venoms of these two species has mainly focused on protein composition, in an attempt to identify the most medically relevant proteins, such as the lethal verrucotoxin and stonustoxin components. This study, however, focused on medically relevant small molecules, and through nuclear magnetic resonance, mass spectroscopy, and fractionation techniques, we discovered and identified the presence of three molecules new to stonefish venom, namely γ-aminobutyric acid (GABA), choline and 0-acetylcholine, and provide the first report of GABA identified in a fish venom. Analysis of the crude venoms on human nicotinic acetylcholine receptors (nAChRs) and a GABA receptor (GABAR) showed S. horrida venom could activate neuronal (α7) and adult muscle-type (α1β1δε) nAChRs, while both crude S. horrida and S. verrucosa venoms activated the GABAR (α1β2γ2). Cytotoxicity studies in immunologically relevant cells (human PBMCs) indicated the venoms possess cell-specific cytotoxicity and analysis of the venom fractions on Na channel subtypes involved in pain showed no activity. This work highlights the need to further investigate the small molecules found in venoms to help understand the mechanistic pathways of clinical symptoms for improved treatment of sting victims, in addition to the discovery of potential drug leads.
玫瑰毒鲉（Synanceia verrucosa）和疣状毒鲉（Synanceia horrida）可以说是地球上毒性最强的鱼类，也是全球人类被严重蜇伤的罪魁祸首。对这两种鱼的毒液研究主要集中在蛋白质组成上，试图确定最具医学相关性的蛋白质，如致命的疣状毒素和石鱼毒素成分。然而，本研究聚焦于具有医学相关性的小分子，通过核磁共振、质谱和分级分离技术，我们发现并鉴定出玫瑰毒鲉毒液中存在三种新分子，即γ-氨基丁酸（GABA）、胆碱和0-乙酰胆碱，并首次报道了在鱼毒中鉴定出GABA。对人烟碱型乙酰胆碱受体（nAChRs）和一种GABA受体（GABAR）上的粗毒液分析表明，疣状毒鲉毒液可激活神经元型（α7）和成年肌肉型（α1β1δε）nAChRs，而疣状毒鲉和玫瑰毒鲉的粗毒液均可激活GABAR（α1β2γ2）。在免疫相关细胞（人外周血单核细胞）中的细胞毒性研究表明，毒液具有细胞特异性细胞毒性，对参与疼痛的钠通道亚型的毒液组分分析显示无活性。这项工作强调，除了发现潜在的药物先导物外，还需要进一步研究毒液中的小分子，以帮助理解临床症状的机制途径，从而改善对蜇伤受害者的治疗。
