Calcium--a central regulator of keratinocyte differentiation in health and disease

Eur J Dermatol. 2014 Nov-Dec;24(6):650-61. doi: 10.1684/ejd.2014.2452.


Regular keratinocyte differentiation is crucial for the formation of an intact epidermal barrier and is triggered by extracellular calcium. Disturbances of epidermal barrier formation and aberrant keratinocyte differentiation are involved in the pathophysiology of several skin diseases, such as psoriasis, atopic dermatitis, basal and squamous skin cancer, and genetic skin diseases such as Darier's disease and Olmstedt syndrome. In this review, we summarize current knowledge about the underlying molecular mechanisms of calcium-induced differentiation in keratinocytes. We provide an overview of calcium's genomic and non-genomic mechanisms to induce differentiation and discuss the calcium gradient in the epidermis, giving rise to cornified skin and lipid envelope formation. We focus on the calcium-sensing receptor, transient receptor potential channels, and STIM/Orai as the major constituents of calcium sensing and calcium entry in the keratinocytes. Finally, skin diseases linked to impaired differentiation will be discussed, paying special attention to disturbed TRP channel expression and TRP channel mutations.

Keywords: TRP channels; calcium; differentiation; keratinocyte.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Calcium / metabolism*
  • Calcium Channels / metabolism
  • Carcinoma, Basal Cell / metabolism
  • Carcinoma, Squamous Cell / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology*
  • Darier Disease / metabolism
  • Dermatitis, Atopic / metabolism
  • Humans
  • Keratinocytes / metabolism
  • Keratinocytes / physiology*
  • Membrane Proteins / metabolism
  • Neoplasm Proteins / metabolism
  • ORAI1 Protein
  • Psoriasis / metabolism
  • Receptors, Calcium-Sensing / metabolism*
  • Skin Diseases / metabolism*
  • Skin Neoplasms / metabolism
  • Stromal Interaction Molecule 1
  • Transient Receptor Potential Channels / metabolism*


  • Calcium Channels
  • Membrane Proteins
  • Neoplasm Proteins
  • ORAI1 Protein
  • ORAI1 protein, human
  • Receptors, Calcium-Sensing
  • STIM1 protein, human
  • Stromal Interaction Molecule 1
  • Transient Receptor Potential Channels
  • Calcium