Importance of transient receptor potential vanilloid 4 (TRPV4) in epidermal barrier function in human skin keratinocytes

  • Naoko Kida
  • Takaaki Sokabe
  • Makiko Kashio
  • Kunitaka Haruna
  • Yuki Mizuno
  • Yasushi Suga
  • Kazuko Nishikawa
  • Akiko Kanamaru
  • Maya Hongo
  • Ai Oba
  • Makoto Tominaga
Ion Channels, Receptors and Transporters


The state of the skin changes drastically depending on the ambient temperature. Skin epidermal keratinocytes express thermosensitive transient receptor potential vanilloid (TRPV) cation channels, TRPV3 and TRPV4. These multimodal receptors are activated by various kinds of chemical and physical stimuli, including warm temperatures (>30°C). It has been suggested that TRPV4 is involved in cell–cell junction maturation; however, the effect of temperature fluctuations on TRPV4-dependent barrier homeostasis is unclear. In the present study, we demonstrated that activation of TRPV4 was crucial for barrier formation and recovery, both of which were critical for the prevention of excess dehydration of human skin keratinocytes. TRPV4 activation by physiological skin temperature (33°C), GSK1016790A or 4α-PDD allowed influx of Ca2+ from extracellular spaces which promoted cell–cell junction development. These changes resulted in augmentation of intercellular barrier integrity in vitro and ex vivo. TRPV4 disruption reduced the increase in trans-epidermal resistance and increased intercellular permeation after a Ca2+ switch. Furthermore, barrier recovery after the disruption of the stratum corneum was accelerated by the activation of TRPV4 either by warm temperature or a chemical activator. Our results suggest that physiological skin temperatures play important roles in cell–cell junction and skin barrier homeostasis through TRPV4 activation.


Transient receptor potential vanilloid 4 Epidermal barrier Temperature Tight junction 



4α-Phorbol 12,13-didecanoate


Transient receptor potential vanilloid 4


Tight junction


Adherens junction


Trans-epidermal water loss


TATA box binding protein


Human epidermal keratinocyte


Trans-epithelial electrical resistance


Stratum corneum





This work was supported by grants to M.T. from the Ministry of Education, Culture, Sports, Science and Technology in Japan. We thank B. Nilius (Katholieke Universiteit, Belgium) for his generous gift of the anti-TRPV4 antibody.

Conflicts of interest


Supplementary material

424_2012_1081_Fig8_ESM.jpg (698 kb)
Fig. S1

Functional expression of TRPV4 in Ca2+-imaging experiments with HEKs. Traces for changes in cytosolic Ca2+ concentrations (340/380 nm ratio) in response to 100 nM GSK1016790A. Bars indicate the duration of stimulation. To confirm the cell viability, ionomycin was applied (JPEG 697 kb)


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Naoko Kida
    • 1
    • 2
  • Takaaki Sokabe
    • 2
  • Makiko Kashio
    • 2
  • Kunitaka Haruna
    • 3
  • Yuki Mizuno
    • 3
  • Yasushi Suga
    • 3
  • Kazuko Nishikawa
    • 1
  • Akiko Kanamaru
    • 1
  • Maya Hongo
    • 1
  • Ai Oba
    • 1
  • Makoto Tominaga
    • 2
    • 4
  1. 1.POLA Chemical Industries, Inc.YokohamaJapan
  2. 2.Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences)National Institutes of Natural SciencesOkazakiJapan
  3. 3.Department of DermatologyJuntendo University Urayasu HospitalUrayasuJapan
  4. 4.Department of Physiological SciencesThe Graduate University for Advanced StudiesOkazakiJapan

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