Abstract
We have shown that cutaneous cooling-sensitive receptors can work as thermostats of skin temperature against cooling. However, molecule of the thermostat is not known. Here, we studied whether cooling-sensitive TRPM8 channels act as thermostats. TRPM8 in HEK293 cells generated output (y) when temperature (T) was below threshold of 28.4°C. Output (y) is given by two equations: At T >28.4°C, y = 0; At T <28.4°C, y = -k(T – 28.4°C). These equations show that TRPM8 is directional comparator to elicits output (y) depending on negative value of thermal difference (ΔT = T – 28.4°C). If negative ΔT-dependent output of TRPM8 in the skin induces responses to warm the skin for minimizing ΔT recursively, TRPM8 acts as thermostats against cooling. With TRPM8-deficient mice, we explored whether TRPM8 induces responses to warm the skin against cooling. In behavioral regulation, when room temperature was 10°C, TRPM8 induced behavior to move to heated floor (35°C) for warming the sole skin. In autonomic regulation, TRPM8 induced activities of thermogenic brown adipose tissue (BAT) against cooling. When menthol was applied to the whole trunk skin at neutral room temperature (27°C), TRPM8 induced a rise in core temperature, which warmed the trunk skin slightly. In contrast, when room was cooled from 27 to 10°C, TRPM8 induced a small rise in core temperature, but skin temperature was severely reduced in both TRPM8-deficient and wild-type mice by a large heat leak to the surroundings. This shows that TRPM8-driven endothermic system is less effective for maintenance of skin temperature against cooling. In conclusion, we found that TRPM8 is molecule of thermostat of skin temperature against cooling.
Highlights
In mammals, thermostat is a key device to maintain body temperature against changes in ambient temperatures
TRPM8 is comparator, but not transducer We examined thermal responses of TRPM8 channels expressed in HEK293 cells by calcium imaging [12]
These results show that TRPM8 induces activities of thermogenic brown adipose tissue (BAT) used for warming the skin in response to cooling
Summary
Thermostat is a key device to maintain body temperature against changes in ambient temperatures. Since Adrian [7], it has been assumed that thermo receptors are transducers (or sensors) that change temperature into the firing-rate code of impulse trains, travelling to the brain Along this line, a target neuron receiving impulses from thermal receptors has been assumed to be ‘‘thermostat’’ that compares skin temperature with a set-point temperature at the level of the firing-rate code, and generates impulses as drive signal inducing thermoregulatory responses [1,3,4,8]. TRPM8, a member of thermo TRP channel family [13], responds to menthol and icilin as well as temperature [10,14] These results deny the assumption that receptors are transducers. By lack of the ‘‘thermostat’’, regulation of skin temperature is not explained
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