Epidermal TRPM8 channel isoform controls the balance between keratinocyte proliferation and differentiation in a cold-dependent manner

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 Ca ²⁺ concentration ([Ca ²⁺] ₘ). In turn, [Ca ²⁺] ₘ modulates ATP and superoxide ([Formula]) synthesis in a cold-dependent manner. We report that this fine tuning of ATP and [Formula] 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. Significance Epidermis, the outer layer of skin, is a protective barrier and a sensing interface. Although deviation of the ambient temperature is one of the most ubiquitous stimuli affecting the skin, the influence of mild cold on epidermal homeostasis is not well understood. Using a large range of techniques, we identified a novel mild-cold sensor protein in keratinocytes and demonstrate its location in the membrane of the endoplasmic reticulum, a major calcium store of the cell, which forms a Ca ²⁺-permeable ion channel. Activation of this channel links the Ca ²⁺ release to mitochondrial Ca ²⁺ uptake and, thereby, modulates synthesis of ATP and superoxide involved in control of epidermal homeostasis. Molecular inactivation of this mild-cold sensor protein in mice impairs normal epidermal homeostasis.