Department of Cancer Biology and Pharmacology, University of I...

TRPM8 is a polymodal nonselective cation channel activated by cold temperature and cooling agents that plays a critical role in the detection of environmental cold We found that TRPM8 is a pharmacological target of tacrolimus FK506 a macrolide immunosuppressant with several clinical uses including the treatment of organ rejection following transplants treatment of atopic dermatitis and dry eye disease Tacrolimus is an inhibitor of the phosphatase calcineurin an action shared with cyclosporine Tacrolimus activates TRPM8 channels in different species including humans and sensitizes their response to cold temperature by inducing a leftward shift in the voltage-dependent activation curve The effects of tacrolimus on purified TRPM8 in lipid bilayers demonstrates conclusively that it has a direct gating effect Moreover the lack of effect of cyclosporine rules out the canonical signaling pathway involving the phosphatase calcineurin Menthol TRPM8-Y745H - and icilin TRPM8-N799A -insensitive mutants were also activated by tacrolimus suggesting a different binding site In cultured mouse DRG neurons tacrolimus evokes an increase in intracellular calcium almost exclusively in cold-sensitive neurons and these responses were drastically blunted in Trpm8 KO mice or after the application of TRPM8 antagonists Cutaneous and corneal cold thermoreceptor endings are also activated by tacrolimus and tacrolimus solutions trigger blinking and cold-evoked behaviors Together our results identify TRPM8 channels in sensory neurons as molecular targets of the immunosuppressant tacrolimus The actions of tacrolimus on TRPM8 resemble those of menthol but likely involve interactions with other channel residues SIGNIFICANCE STATEMENT TRPM8 is a polymodal TRP channel involved in cold temperature sensing thermoregulation and cold pain TRPM8 is also involved in the pathophysiology of dry eye disease and TRPM8 activation has antiallodynic and antipruritic effects making it a prime therapeutic target in several cutaneous and neural diseases We report the direct agonist effect of tacrolimus a potent natural immunosuppressant with multiple clinical applications on TRPM8 activity This interaction represents a novel neuroimmune interface The identification of a clinically approved drug with agonist activity on TRPM8 channels could be used experimentally to probe the function of TRPM8 in humans Our findings may explain some of the sensory and anti-inflammatory effects described for this drug in the skin and the eye surface

Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, 1 Illini Drive, Peoria, Illinois 61605.

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The Immunosuppressant Macrolide Tacrolimus Activates Cold-Sensing TRPM8 Channels