Peptide from Sea Anemone Metridium senile Affects Transient Receptor Potential Ankyrin-repeat 1 (TRPA1) Function and Produces Analgesic Effect

Yulia A Logashina,Irina V Mosharova,Yulia V Korolkova,Irina V Shelukhina,Igor A Dyachenko,Victor A Palikov,Yulia A Palikova,Arkadii N Murashev,Sergey A Kozlov,Klara Stensvåg,Yaroslav A Andreev

doi:10.1074/jbc.m116.757369

Abstract

The transient receptor potential ankyrin-repeat 1 (TRPA1) is an important player in pain and inflammatory pathways. It is a promising target for novel drug development for the treatment of a number of pathological states. A novel peptide producing a significant potentiating effect on allyl isothiocyanate- and diclofenac-induced currents of TRPA1 was isolated from the venom of sea anemone Metridium senile. It is a 35-amino acid peptide cross-linked by two disulfide bridges named τ-AnmTX Ms 9a-1 (short name Ms 9a-1) according to a structure similar to other sea anemone peptides belonging to structural group 9a. The structures of the two genes encoding the different precursor proteins of Ms 9a-1 were determined. Peptide Ms 9a-1 acted as a positive modulator of TRPA1 in vitro but did not cause pain or thermal hyperalgesia when injected into the hind paw of mice. Intravenous injection of Ms 9a-1 (0.3 mg/kg) produced a significant decrease in the nociceptive and inflammatory response to allyl isothiocyanate (the agonist of TRPA1) and reversed CFA (Complete Freund's Adjuvant)-induced inflammation and thermal hyperalgesia. Taken together these data support the hypothesis that Ms 9a-1 potentiates the response of TRPA1 to endogenous agonists followed by persistent functional loss of TRPA1-expressing neurons. We can conclude that TRPA1 potentiating may be useful as a therapeutic approach as Ms 9a-1 produces significant analgesic and anti-inflammatory effects in mice models of pain.

Highlights

The transient receptor potential ankyrin-repeat 1 (TRPA1) is an important player in pain and inflammatory pathways
Peptide Isolation and Primary Structure Determination— The crude peptide fraction of M. senile venom produced a potentiating effect on agonist-activated rTRPA1 response in fluorescent inflow calcium assay on stable CHO cell lines expressing the receptor
The C-terminal residue was predicted as Ser by the difference between calculated molecular weight of the sequenced fragment and molecular weight of peptide measured by matrix-assisted laser desorption ionization (MALDI)

Summary

Introduction

The transient receptor potential ankyrin-repeat 1 (TRPA1) is an important player in pain and inflammatory pathways. A novel peptide producing a significant potentiating effect on allyl isothiocyanate- and diclofenac-induced currents of TRPA1 was isolated from the venom of sea anemone Metridium senile. Peptide Ms 9a-1 acted as a positive modulator of TRPA1 in vitro but did not cause pain or thermal hyperalgesia when injected into the hind paw of mice.

Results

Conclusion