Crotalphine desensitizes TRPA1 ion channels to alleviate inflammatory hyperalgesia

Author(s):Show less -

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.

• Document type: Journal article
• Source: Pain; v. 157, n. 11, p. 2504-2516, NOV 2016.
• Web of Science Citations: 11

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. (AU)

• FAPESP's process: 08/57898-0 - National Institute of Science and Technology on Toxins
• Grantee: Osvaldo Augusto Brazil Esteves Sant'Anna
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/51458-4 - Effect of crotalfine on ion channels in sensory neurons
• Grantee: Yara Cury
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling
• Grantee: Hugo Aguirre Armelin
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 98/14307-9 - Center for Applied Toxinology
• Grantee: Hugo Aguirre Armelin
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC