Crotalphine desensitizes TRPA1 ion channels to alleviate inflammatory hyperalgesia

Bressan, Elisangela, Touska, Filip, Vetter, Irina, Kistner, Katrin, Kichko, Tatjana I., Teixeira, Nathalia B., Picolo, Gisele, Cury, Yara, Lewis, Richard J., Fischer, Michael J. M., Zimmermann, Katharina and Reeh, Peter W. (2016) Crotalphine desensitizes TRPA1 ion channels to alleviate inflammatory hyperalgesia. Pain, 157 11: 2504-2516. doi:10.1097/j.pain.0000000000000669


Author Bressan, Elisangela
Touska, Filip
Vetter, Irina
Kistner, Katrin
Kichko, Tatjana I.
Teixeira, Nathalia B.
Picolo, Gisele
Cury, Yara
Lewis, Richard J.
Fischer, Michael J. M.
Zimmermann, Katharina
Reeh, Peter W.
Title Crotalphine desensitizes TRPA1 ion channels to alleviate inflammatory hyperalgesia
Journal name Pain   Check publisher's open access policy
ISSN 1872-6623
0304-3959
Publication date 2016-11-01
Year available 2016
Sub-type Article (original research)
DOI 10.1097/j.pain.0000000000000669
Open Access Status Not yet assessed
Volume 157
Issue 11
Start page 2504
End page 2516
Total pages 13
Place of publication Philadelphia, PA, United States
Publisher Lippincott Williams & Wilkins
Language eng
Abstract Crotalphine is a structural analogue to a novel analgesic peptide that was first identified in the crude venom from the South American rattlesnake Crotalus durissus terrificus. Although crotalphine's analgesic effect is well established, its direct mechanism of action remains unresolved. The aim of the present study was to investigate the effect of crotalphine on ion channels in peripheral pain pathways. We found that picomolar concentrations of crotalphine selectively activate heterologously expressed and native TRPA1 ion channels. TRPA1 activation by crotalphine required intact N-terminal cysteine residues and was followed by strong and long-lasting desensitization of the channel. Homologous desensitization of recombinant TRPA1 and heterologous desensitization in cultured dorsal root ganglia neurons was observed. Likewise, crotalphine acted on peptidergic TRPA1-expressing nerve endings ex vivo as demonstrated by suppression of calcitonin gene-related peptide release from the trachea and in vivo by inhibition of chemically induced and inflammatory hypersensitivity in mice. The crotalphine-mediated desensitizing effect was abolished by the TRPA1 blocker HC030031 and absent in TRPA1-deficient mice. Taken together, these results suggest that crotalphine is the first peptide to mediate antinociception selectively and at subnanomolar concentrations by targeting TRPA1 ion channels.
Formatted abstract
Crotalphine is a structural analogue to a novel analgesic peptide that was first identified in the crude venom from the South American rattlesnake Crotalus durissus terrificus. Although crotalphine's analgesic effect is well established, its direct mechanism of action remains unresolved. The aim of the present study was to investigate the effect of crotalphine on ion channels in peripheral pain pathways. We found that picomolar concentrations of crotalphine selectively activate heterologously expressed and native TRPA1 ion channels. TRPA1 activation by crotalphine required intact N-terminal cysteine residues and was followed by strong and longlasting desensitization of the channel. Homologous desensitization of recombinant TRPA1 and heterologous desensitization in cultured dorsal root ganglia neurons was observed. Likewise, crotalphine acted on peptidergic TRPA1-expressing nerve endings ex vivo as demonstrated by suppression of calcitonin gene-related peptide release from the trachea and in vivo by inhibition of chemically induced and inflammatory hypersensitivity in mice. The crotalphine-mediated desensitizing effect was abolished by the TRPA1 blocker HC030031 and absent in TRPA1-deficient mice. Taken together, these results suggest that crotalphine is the first peptide to mediate antinociception selectively and at subnanomolar concentrations by targeting TRPA1 ion channels.
Keyword Bradykinin
CGRP
Ciguatoxin
Crotalphine
Desensitization
TRPA1
Zymosan
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID Zi 1172/2-1
08/57898-0
573790/2008-6
1998/14307-9
2012/51458-4
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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