Merkel cells sense cooling with TRPM8 channels.

In the skin, Merkel cells (MCs) connect with keratinocytes and Aβ nerve fibers to form a touch receptor which functions as a slow adapting mechanoreceptor (SA1 receptor). In human and mouse MCs, we observed an increased concentration of intracellular Ca(2+) ions in response to cold temperature and transient receptor potential melastatine 8 (TRPM8) ion channel agonists. A reduction in the response to cooling and TRPM8 agonists occurred following addition of TRPM8 antagonists, as well as in TRPM8 knockout mice. Cold temperature and TRPM8 agonists also induced a current which was inhibited by a TRPM8 antagonist. Our results indicate that MCs sense cooling through TRPM8 channels. We hypothesized that cooling modulates the SA1 response. Cooling mouse skin to 22°C reduced the SA1 discharge frequency. Interestingly, we observed no such reduction in TRPM8 knockout mice. Similarly, in human skin, a temperature of 22°C applied to the SA1 receptive field reduced the spiking discharge. Altogether, our results indicate that MCs are polymodal sensory cells which respond to mild cold stimuli through the activation of TRPM8 channels. Thermal activation of MCs, and possibly other TRPM8-expressing non-neuronal cells such as keratinocytes, potentially adapts the discharge of SA1 receptors during cooling.