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.

► Breathlessness or dyspnea relief is an important goal in chronic obstructive lung disease. ► Neuromechanical uncoupling is the mismatch of command to breathe (effort) vs the afferent ‘response’. ► Airway sensory afferents represent novel therapeutic opportunities for dyspnea treatment. ► The sensory TRPM8 ion channel is gated by cold temperatures in the range of ≈25–28°C. ► Evidence suggests TRPM8 temperature and menthol responses mediate airway afferent activation. ► TRPM8 in the airways may be a novel afferent target in dyspnea of COPD and in cold-induced asthma.