| Over the last sixteen years, a number of nonselective cation channels belonging to the transient receptor potential (TRP) family have been found to play instrumental roles in thermosensation. The two most prominent thermosensory TRP channels are TRPV1, which responds to noxious heat and heat mimetics such as capsaicin (the active ingredient in chili peppers), and TRPM8, which responds to cold and cold mimetics such as menthol (the active ingredient in mint). These channels are highly expressed in sensory afferents innervating the skin and knockout studies have implicated them in both acute thermosensation and the development of thermal hypersensitivity. Although the role of these channels in thermosensation is firmly established, we currently know little in regards to the causal intracellular mechanisms controlling thermal hypersensitivity. Furthermore, there are no TRP channel-specific treatments for sensory- related conditions that do not have serious side effects. This area of research is complicated by the fact that many TRP family channels have been found in areas of the body that are not exposed to the temperatures necessary for their activation, suggesting roles for these channels in other cellular processes.;Here we identify a novel role of the cold-sensitive channel TRPM8 in insulin homeostasis. We find that Trpm8-/- mice have heightened insulin clearance compared to wildtype, a phenotype that also correlates with increased insulin degrading enzyme (IDE) in the liver, the predominant organ involved in insulin clearance. Furthermore, as previous studies have shown that TRPV1+ afferents in the hepatic portal vein (HPV) are instrumental in glucose sensing, the presence of TRPM8+ sensory afferents in the HPV suggests that TRPM8-expressing neurons may be influencing liver insulin clearance by controlling localized expression of IDE.;In addition to identifying a new role of TRPM8 outside of thermosensation, we show that TRPM8 pore dilation can be used to selectively target the large cationic dye PO-PRO3 to cold-sensing neurons, a finding that refutes previous work claiming that TRPM8 does not allow such large cationic molecule permeation. These results provide proof of principle for this technique to be used to selectively block cold sensing neurons using the positively charged lidocaine derivative QX-314.;Finally, to better understand what is going on inside of cold-sensing neurons, we have developed a transgenic mouse line that enables the specific immunoprecipitation of actively translating transcripts from TRPM8-expressing cells.;The data we present here furthers our understanding of TRPM8, its role outside of thermosensation, and opens the door to a new therapeutic methodology for the treatment of chronic cold hypersensitivity. Future studies using the tools developed herein will help to identify targets and pathways involved in cold sensation and aid in the development of new treatments for various sensory-related conditions. |
