Fine-tuning of eTRPM8 expression and activity conditions keratinocyte fate

Channels (Austin). 2016 Jul 3;10(4):320-31. doi: 10.1080/19336950.2016.1168551. Epub 2016 Mar 25.


Recently, we reported the cloning and characterization of short isoform of the icilin-activated cold receptor TRPM8 channel in keratinocytes, dubbed eTRPM8. We demonstrated that eTRPM8 via fine tuning of the endoplasmic reticulum (ER) - mitochondria Ca(2+) shuttling regulates mitochondrial ATP and superoxide (O2(•-)) production and, thereby, mediates control of epidermal homeostasis by mild cold. Here, we provide additional information explaining why eTRPM8 suppression and TRPM8 stimulation both inhibit keratinocyte growth. We also demonstrate that stimulation of eTRPM8 with icilin may give rise to sustained oscillatory responses. Furthermore, we show that ATP-induced cytosolic and mitochondrial Ca(2+) responses are attenuated by eTRPM8 suppression. This suggests positive interplay between eTRPM8 and purinergic signaling pathways, what may serve to facilitate the ER-mitochondria Ca(2+) shuttling. Finally, we demonstrate that cold (25°C) induces eTRPM8-dependent superoxide-mediated necrosis of keratinocytes. Altogether, these results are in line with our model of eTRPM8-mediated cold-dependent balance between keratinocyte proliferation and differentiation.

Keywords: ATP; ER Calcium fluxes; ROS; TRPM8 channels; bioenergetics; cell death; cell physiology; differentiation; eTRPM8; epidermal homeostasis; mild cold; mitochondria; proliferation; superoxide.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Calcium / metabolism*
  • Cell Line
  • Cell Proliferation
  • Cytosol / metabolism
  • Endoplasmic Reticulum / metabolism
  • Epidermal Cells
  • Epidermis / metabolism
  • Gene Expression
  • Homeostasis
  • Humans
  • Keratinocytes / cytology*
  • Keratinocytes / metabolism*
  • Mice
  • Mitochondria / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Signal Transduction
  • Superoxides / metabolism
  • TRPM Cation Channels / genetics*
  • TRPM Cation Channels / metabolism*


  • Protein Isoforms
  • TRPM Cation Channels
  • TRPM8 protein, human
  • Superoxides
  • Adenosine Triphosphate
  • Calcium