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TRPM8 inhibits substance P release from primary sensory neurons via PKA/GSK-3beta to protect colonic epithelium in colitis.
Zhang et al., Cell Death Dis 2024
DOI: 10.1038/s41419-024-06480-5
Ho-ho-ho! Gather ’round, my curious elves, for a tale of icy receptors and fiery peptides in the wondrous world of human biology. In the frosty realm of our bodies, there exists a chilly sentinel known as Transient receptor potential melastatin 8 (TRPM8), much like myself, sensing the cold, but instead of bringing joy, it oversees our sensations of frostiness. Now, this tale intertwines with a spicy character, Substance P (SP), a neuropeptide that, unlike the comforting warmth of a Yuletide fire, stokes the flames of inflammation within us.
Our intrepid scientists, much like elves in their workshop, delved into the mysteries of how TRPM8 might rein in SP’s fiery nature, particularly during the blizzard of discomfort known as colitis. They scoured the Gene Expression Omnibus dataset, a list even longer than my Naughty or Nice list, to find clues among those with inflammatory bowel disease.
Using a concoction called Dextran sulfate sodium (DSS), they induced colitis in mice, much like how I induce joy with presents. They also studied mouse dorsal root ganglion (DRG) neurons, the ND7/23 cell line, and both mouse and human colonic organoids, which are like tiny snow globes of gut tissue.
What they found was as striking as a sleigh bell’s chime: TRPM8, along with TAC1 and WNT3A, were like the three reindeer leading the sleigh of ulcerative colitis severity. Now, here’s where the magic happens: a minty TRPM8 agonist, menthol (think candy canes), and a SP receptor antagonist, Aprepitant (not as tasty), could both ease colitis in mice. But combining them, much like mixing reindeer and jet engines, didn’t add any extra oomph.
Menthol, it seems, opens the floodgates for calcium ions in mouse DRG neurons, while also playing the role of a mischievous elf by disrupting the naughty partnership between PKAca and GSK-3β. This, in turn, keeps Wnt3a-driven β-catenin from egging on SP to cause trouble. And what of SP’s effect on the colonic epithelium? Well, like a lump of coal, it hampers growth and encourages apoptosis, which is as unwelcome as a stocking full of soot.
In the end, our story concludes with TRPM8 donning the red suit and hat, heroically inhibiting SP’s release and its role in promoting colonic epithelial apoptosis, thus bringing relief to colitis, much like I bring joy to the world on Christmas Eve. And with that, my dear elves, our narrative comes to a close. May your days be merry, bright, and inflammation-free!