Heat-evoked activation of TRPM2: A novel molecular target of cyclic ADP-ribose at body temperature

Abstract

Temperature sensing ability is underlain by TRPV, TRPM and TRPA cation channels.Here we show heat-evoked activation of the TRPM2 channel, which has been reported to be activated by β-NAD⁺, ADP-ribose, and redox status change. TRPM2 activation had threshold of approximately 35°C and was maximally induced at about 36°C. When heat stimulus was given in the presence of intracellularly applied β-NAD⁺ or ADP-ribose, TRPM2 activity was dramatically potentiated, compared to the activity induced by heat, β-NAD⁺ or ADP-ribose alone. Furthermore, cyclic ADP-ribose elicited similar enhancement of heat-evoked TRPM2 activity. The heat-evoked TRPM2 responses were also observed in inside-out configuration, indicating direct gating of TRPM2 by heat. Similar native heat-evoked channel responses were observed in rat insulinoma RIN-5F cells. TRPM2 was expressed in RIN-5F cells, and co-expressed with insulin in mouse pancreatic β-cells. These results indicate that body temperature regulates Ca²⁺ entry into cells that express TRPM2 and that TRPM2 functions as the first molecular target of cyclic ADP-ribose on plasma membrane. [Jpn J Physiol 54 Suppl:S67 (2004)]