TRPM8 channel is involved in the ventilatory response to CO mediating hypercapnic Ca responses.

The role of TRP channels in the ventilatory response to CO 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 Ca responses of TRPM8-overexpressing HEK-293 cells to hypercapnic acidosis. Subpopulations of cells that exhibited hypercapnic acidosis-induced Ca response also responded to the application of menthol. These results suggest that TRPM8 partially mediates the ventilatory response to CO via changes in intracellular Ca and is a chemosensing protein that may be involved in detecting endogenous CO production.