Universität zu Köln

van Cann, Marianne, Kuzmenkov, Alexey, Isensee, Jorg, Andreev-Andrievskiy, Alexander ORCID: 0000-0002-1173-8153, Peigneur, Steve, Khusainov, Georgii, Berkut, Antonina, Tytgat, Jan, Vassilevski, Alexander ORCID: 0000-0002-1359-0076 and Hucho, Tim . Scorpion toxin MeuNaTx alpha-1 sensitizes primary nociceptors by selective modulation of voltage-gated sodium channels. FEBS J.. HOBOKEN: WILEY. ISSN 1742-4658

Full text not available from this repository.

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 MeuNaTx alpha-1, a sodium channel-selective scorpion alpha-toxin from Mesobuthus eupeus, which affected both PKA-II and ERK1/2. Recombinant MeuNaTx alpha-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 MeuNaTx alpha-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 Na(V)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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code van Cann, Marianne UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuzmenkov, Alexey UNSPECIFIED UNSPECIFIED UNSPECIFIED Isensee, Jorg UNSPECIFIED UNSPECIFIED UNSPECIFIED Andreev-Andrievskiy, Alexander UNSPECIFIED orcid.org/0000-0002-1173-8153 UNSPECIFIED Peigneur, Steve UNSPECIFIED UNSPECIFIED UNSPECIFIED Khusainov, Georgii UNSPECIFIED UNSPECIFIED UNSPECIFIED Berkut, Antonina UNSPECIFIED UNSPECIFIED UNSPECIFIED Tytgat, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Vassilevski, Alexander UNSPECIFIED orcid.org/0000-0002-1359-0076 UNSPECIFIED Hucho, Tim UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-312125
DOI:	10.1111/febs.15593
Journal or Publication Title:	FEBS J.
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1742-4658
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SPINAL SENSORY NEURONS; SPIDER TOXINS; VENOM; PAIN; NEUROTOXINS; PHOSPHORYLATION; ACTIVATION; EPIDEMIC; BINDING; UPDATE Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/31212