1. Scorpion toxin MeuNaTxα-1 sensitizes primary nociceptors by selective modulation of voltage-gated sodium channels.
- Author
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van Cann M, Kuzmenkov A, Isensee J, Andreev-Andrievskiy A, Peigneur S, Khusainov G, Berkut A, Tytgat J, Vassilevski A, and Hucho T
- Subjects
- Animals, Animals, Newborn, Humans, Hyperalgesia genetics, Hyperalgesia pathology, MAP Kinase Signaling System drug effects, Mice, Oocytes drug effects, Oocytes growth & development, Rats, Scorpion Venoms chemistry, Scorpion Venoms pharmacology, Scorpions chemistry, Sensory Receptor Cells, Xenopus laevis growth & development, Cyclic AMP-Dependent Protein Kinase Type II genetics, NAV1.2 Voltage-Gated Sodium Channel genetics, Pain genetics, Voltage-Gated Sodium Channels genetics
- Abstract
Venoms are a rich source of highly specific toxins, which allow the identification of novel therapeutic targets. We have now applied high content screening (HCS) microscopy to identify toxins that modulate pain sensitization signaling in primary sensory neurons of rat and elucidated the underlying mechanism. A set of venoms and fractions thereof were analyzed for their ability to activate type II protein kinase A (PKA-II) and extracellular signal-regulated kinases (ERK1/2). We identified MeuNaTxα-1, a sodium channel-selective scorpion α-toxin from Mesobuthus eupeus, which affected both PKA-II and ERK1/2. Recombinant MeuNaTxα-1 showed identical activity to the native toxin on mammalian voltage-gated sodium channels expressed in Xenopus laevis oocytes and induced thermal hyperalgesia in adult mice. The effect of MeuNaTxα-1 on sensory neurons was dose-dependent and tetrodotoxin-sensitive. Application of inhibitors and toxin mutants with altered sodium channel selectivity demonstrated that signaling activation in sensory neurons depends on Na
V 1.2 isoform. Accordingly, the toxin was more potent in neurons from newborn rats, where NaV 1.2 is expressed at a higher level. Our results demonstrate that HCS microscopy-based monitoring of intracellular signaling is a novel and powerful tool to identify and characterize venoms and their toxins affecting sensory neurons., (© 2020 Federation of European Biochemical Societies.)- Published
- 2021
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