TRPM8 and dyspnea: from the frigid and fascinating past to the cool future?

The transient receptor potential melastatin 8 (TRPM8) ion channel is gated by cool and noxious cold temperatures. The activation threshold is in the range of ≈25-28°C, which aligns well with the discharge of airway afferents. TRPM8 is widely expressed across species and evolutionary changes in the TRPM8 amino acid sequence may tune the temperatures at which it is gated. The discovery of TRPM8 and its molecular/biophysical characterization provides a robust candidate for airway afferents responding to cool/cold temperatures. TRPM8 may provide a mechanistic link for the manipulation of respiratory sensations such as dyspnea or mechanisms leading to cold-induced asthma and cough.