Anti-inflammatory effects of FS48, the first potassium channel inhibitor from the salivary glands of the flea Xenopsylla cheopis.
Animals
Anti-Inflammatory Agents
/ pharmacology
Edema
/ drug therapy
Female
Humans
Inflammation
/ drug therapy
Kv1.3 Potassium Channel
/ antagonists & inhibitors
Macrophages
/ drug effects
Male
Mice
NF-kappa B
/ metabolism
Salivary Glands
/ metabolism
Scorpion Venoms
/ chemistry
Signal Transduction
Tumor Necrosis Factor-alpha
/ metabolism
Xenopsylla
Kv1.3
Xenopsylla cheopis
inflammation
macrophage
potassium channel
salivary gland
venom
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
Historique:
received:
13
11
2020
revised:
07
04
2021
accepted:
13
04
2021
pubmed:
18
4
2021
medline:
24
8
2021
entrez:
17
4
2021
Statut:
ppublish
Résumé
The voltage-gated potassium (Kv) 1.3 channel plays a crucial role in the immune responsiveness of T-lymphocytes and macrophages, presenting a potential target for treatment of immune- and inflammation related-diseases. FS48, a protein from the rodent flea Xenopsylla cheopis, shares the three disulfide bond feature of scorpion toxins. However, its three-dimensional structure and biological function are still unclear. In the present study, the structure of FS48 was evaluated by circular dichroism and homology modeling. We also described its in vitro ion channel activity using patch clamp recording and investigated its anti-inflammatory activity in LPS-induced Raw 264.7 macrophage cells and carrageenan-induced paw edema in mice. FS48 was found to adopt a common αββ structure and contain an atypical dyad motif. It dose-dependently exhibited the Kv1.3 channel in Raw 264.7 and HEK 293T cells, and its ability to block the channel pore was demonstrated by the kinetics of activation and competition binding with tetraethylammonium. FS48 also downregulated the secretion of proinflammatory molecules NO, IL-1β, TNF-α, and IL-6 by Raw 264.7 cells in a manner dependent on Kv1.3 channel blockage and the subsequent inactivation of the MAPK/NF-κB pathways. Finally, we observed that FS48 inhibited the paw edema formation, tissue myeloperoxidase activity, and inflammatory cell infiltrations in carrageenan-treated mice. We therefore conclude that FS48 identified from the flea saliva is a novel potassium channel inhibitor displaying anti-inflammatory activity. This discovery will promote understanding of the bloodsucking mechanism of the flea and provide a new template molecule for the design of Kv1.3 channel blockers.
Identifiants
pubmed: 33864815
pii: S0021-9258(21)00459-2
doi: 10.1016/j.jbc.2021.100670
pmc: PMC8131326
pii:
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Kv1.3 Potassium Channel
0
NF-kappa B
0
Scorpion Venoms
0
Tumor Necrosis Factor-alpha
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100670Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
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