FK506 (tacrolimus) causes pain sensation through the activation of transient receptor potential ankyrin 1 (TRPA1) channels
FK506 (tacrolimus) is an immunosuppressant widely used as an ointment in the treatment of atopic dermatitis. However, local application of FK506 can evoke burning sensations in atopic dermatitis patients, and its mechanisms are unknown. In this study, we found that FK506 activates transient receptor potential ankyrin 1 (TRPA1) channels. In Ca2+-imaging experiments, increases in intracellular Ca2+ concentrations ([Ca2+]i) by FK506 were observed in HEK293T cells expressing hTRPA1 or hTRPM8. FK506-induced currents were observed in HEK293T cells expressing hTRPA1 or mTRPA1, but less or not at all in cells expressing hTRPV1 or hTRPM8 using a patch-clamp technique. FK506 also evoked single-channel opening of hTRPA1 in an inside-out configuration. FK506-induced [Ca2+]i increases were also observed in TRPA1-expressing mouse primary sensory neurons. Furthermore, injection of FK506 evoked licking or biting behaviors and these behaviors were almost abolished in TRPA1 knockout mice. These results indicate that FK506 might cause pain sensations through TRPA1 activation.
KeywordsFK506 Pain TRPA1 Sensory neuron Adverse effect
We thank Dr. Mitsutoki Hatta from Fukuoka Dental College for helpful discussion, and Ms. N. Fukuta from the National Institute for Physiological Sciences for technical assistance.
The present study was supported by a grant from Maruho Co., Ltd.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
Statement on the welfare of animals
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
- 11.Cury Martins J, Martins C, Aoki V, Gois AF, Ishii HA, da Silva EM (2015) Topical tacrolimus for atopic dermatitis. Conhrane Datab Syst Rev 7:Cd009864Google Scholar
- 12.Reitamo S, Wollenberg A, Schopf E, Perrot JL, Marks R, Ruzicka T, Christophers E, Kapp A, Lahfa M, Rubins A, Jablonska S, Rustin M (2000) Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study Group. Arch Dermatol 136:999–1006CrossRefGoogle Scholar
- 14.Reitamo S, Rustin M, Ruzicka T, Cambazard F, Kalimo K, Friedmann PS, Schoepf E, Lahfa M, Diepgen TL, Judodihardjo H, Wollenberg A, Berth-Jones J, Bieber T, European Tacrolimus Ointment Study G (2002) Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with atopic dermatitis. J Allergy Clin Immunol 109:547–555CrossRefGoogle Scholar
- 18.Tominaga M (2007) The role of TRP channels in thermosensation. In: Liedtke WB, Heller S (eds) TRP ion channel function in sensory transduction and cellular signaling cascades. CRC Press, Boca RatonGoogle Scholar
- 29.Peyrot des Gachons C, Uchida K, Bryant B, Shima A, Sperry JB, Dankulich-Nagrudny L, Tominaga M, Smith AB 3rd, Beauchamp GK, Breslin PA (2011) Unusual pungency from extra-virgin olive oil is attributable to restricted spatial expression of the receptor of oleocanthal. J Neurosci 31:999–1009CrossRefGoogle Scholar
- 31.Corey DP, Garcia-Anoveros J, Holt JR, Kwan KY, Lin SY, Vollrath MA, Amalfitano A, Cheung EL, Derfler BH, Duggan A, Geleoc GS, Gray PA, Hoffman MP, Rehm HL, Tamasauskas D, Zhang DS (2004) TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature 432:723–730CrossRefGoogle Scholar
- 51.Zimmermann K, Lennerz JK, Hein A, Link AS, Kaczmarek JS, Delling M, Uysal S, Pfeifer JD, Riccio A, Clapham DE (2011) Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system. Proc Natl Acad Sci USA 108:18114–18119CrossRefGoogle Scholar