Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 26, Pages E3345-E3354Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1423357112
Keywords
eTRPM8; cold; epidermal homeostasis; calcium; mitochondria bioenergetics
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Funding
- Institut National de la Recherche Medicale
- Ministere de l'Education Nationale
- Ligue Nationale Contre le Cancer
- Region Nord-Pas-de-Calais
- Agence Nationale de Recherche Grant REPROD
- Cosmetics Department of Johnson & Johnson Laboratories
- Fondation pour la Recherche Medicale
- State Foundation for Fundamental Research [F 46.2/001]
- French association Fondation pour la Recherche Medicale
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Deviation of the ambient temperature is one of the most ubiquitous stimuli that continuously affect mammals' skin. Although the role of the warmth receptors in epidermal homeostasis (EH) was elucidated in recent years, the mystery of the keratinocyte mild-cold sensor remains unsolved. Here we report the cloning and characterization of a new functional epidermal isoform of the transient receptor potential M8 (TRPM8) mild-cold receptor, dubbed epidermal TRPM8 (eTRPM8), which is localized in the keratinocyte endoplasmic reticulum membrane and controls mitochondrial Ca2+ concentration ([Ca2+](m)). In turn, [Ca2+](m) modulates ATP and superoxide (O-2(center dot-)) synthesis in a cold-dependent manner. We report that this fine tuning of ATP and O-2(center dot-) levels by cooling controls the balance between keratinocyte proliferation and differentiation. Finally, to ascertain eTRPM8's role in EH in vivo we developed a new functional knockout mouse strain by deleting the pore domain of TRPM8 and demonstrated that eTRPM8 knockout impairs adaptation of the epidermis to low temperatures.
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