TRPM8 channel is involved in the ventilatory response to CO2 mediating hypercapnic Ca2+ responses

The role of TRP channels in the ventilatory response to CO2 was investigated in vivo. To this end, the respiration of unrestrained adult TRPM8-, TRPV1- and TRPV4-channel knockout mice was measured using whole-body plethysmography. Under control conditions and hyperoxic hypercapnia, no difference in respiratory parameters was observed between adult wild-type mice and TRPV1- and TRPV4-channel knockout mice. However, TRPM8-channel knockout mice showed decreased tidal volume under both hypercapnia and resting conditions. In addition, the expression of TRPM8, TRPV1 and TRPV4 mRNAs was detected in EGFP-positive glial cells in the medulla of GFAP promoter-EGFP transgenic mice by real-time PCR. Furthermore, we measured intracellular Ca2+ responses of TRPM8-overexpressing HEK-293 cells to hypercapnic acidosis. Subpopulations of cells that exhibited hypercapnic acidosis-induced Ca2+ response also responded to the application of menthol. These results suggest that TRPM8 partially mediates the ventilatory response to CO2 via changes in intracellular Ca2+ and is a chemosensing protein that may be involved in detecting endogenous CO2 production.