cooling-sensitive trpm8 is thermostat of skin temperature against coolingcooling-sensitive trpm8是皮肤温度与冷却的恒温器.pdfVIP

Cooling-Sensitive TRPM8 Is Thermostat of Skin Temperature against Cooling 1 1 1 2 3 Koji Tajino , Hiroshi Hosokawa , Shingo Maegawa , Kiyoshi Matsumura , Ajay Dhaka , Shigeo Kobayashi1* 1 Department of Intelligence Science and Technology, Graduate School of Informatics, Kyoto University, Kyoto, Japan, 2 Faculty of Information Science and Technology, Osaka Institute of Technology, Hirakata, Osaka, Japan, 3 Department of Biological Structure, University of Washington, Seattle, Washington, United States of America 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 28.4uC. Output (y) is given by two equations: At T .28.4uC, y = 0; At T ,28.4uC, y = -k(T – 28.4uC). These equations show that TRPM8 is directional comparator to elicits output (y) depending on negative value of thermal difference (DT = T – 28.4uC). If negative DT-dependent output of TRPM8 in the skin induces responses to warm the skin for minimizing DT 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 10uC, TRPM8 induced behavior to move to heated floor (35uC) 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 (27uC), TRPM8 induced a rise in core tem