Cholesterol sensitises the transient receptor potential channel TRPV3 to lower temperatures and activator concentrations.

TRPV3, a thermosensitive cation channel, is predominantly expressed in keratinocytes. It contributes to physiological processes such as thermosensation, nociception, and skin development. TRPV3 is polymodally regulated by chemical agonists, innocuous heat, intracellular acidification or by membrane depolarization. By manipulating the content of plasma membrane cholesterol, a key modulator of the physicochemical properties of biological membranes, we here addressed the question, how the lipid environment influences TRPV3. Cholesterol supplementation robustly potentiated TRPV3 channel activity by sensitising it to lower concentrations of chemical activators. In addition, the thermal activation of TRPV3 is significantly shifted to lower temperatures in cholesterol-enriched cells. The sensitising effect of cholesterol was not caused by an increased plasma membrane targeting of the channel. In HaCaT keratinocytes, which natively express TRPV3, a cholesterol-mediated sensitisation of TRPV3-like responses was reproduced. The cholesterol-dependent modulation of TRPV3 activity may provide a molecular mechanism to interpret its involvement in keratinocyte differentiation.