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The Journal of Physiological Sciences

, Volume 69, Issue 2, pp 305–316 | Cite as

FK506 (tacrolimus) causes pain sensation through the activation of transient receptor potential ankyrin 1 (TRPA1) channels

  • Tomo Kita
  • Kunitoshi UchidaEmail author
  • Kenichi Kato
  • Yoshiro Suzuki
  • Makoto Tominaga
  • Jun Yamazaki
Original Paper

Abstract

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.

Keywords

FK506 Pain TRPA1 Sensory neuron Adverse effect 

Notes

Acknowledgements

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.

Funding

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.

Supplementary material

12576_2018_647_MOESM1_ESM.pdf (516 kb)
Supplementary material 1 (PDF 516 kb)
12576_2018_647_MOESM2_ESM.docx (14 kb)
Supplementary material 2 (DOCX 13 kb)

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Copyright information

© The Physiological Society of Japan and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Tomo Kita
    • 1
  • Kunitoshi Uchida
    • 1
    Email author
  • Kenichi Kato
    • 1
  • Yoshiro Suzuki
    • 2
  • Makoto Tominaga
    • 2
    • 3
  • Jun Yamazaki
    • 1
  1. 1.Department of Physiological Science and Molecular BiologyFukuoka Dental CollegeFukuokaJapan
  2. 2.Division of Cell Signaling, National Institute for Physiological SciencesNational Institutes of Natural SciencesOkazakiJapan
  3. 3.Thermal Biology Group, Exploratory Research Center on Life and Living SystemsNational Institutes of Natural SciencesOkazakiJapan

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