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The immunosuppressant macrolide tacrolimus activates cold-sensing TRPM8 channels.

  • Arcas, José Miguel1
  • González, Alejandro1
  • Gers-Barlag, Katharina1
  • González-González, Omar1, 2
  • Bech, Federico1, 2
  • Demirkhanyan, Lusine3
  • Zakharian, Eleonora3
  • Belmonte, Carlos1, 2
  • Gomis, Ana1
  • Viana, Félix4
  • 1 Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, 03550 San Juan de Alicante, Spain. , (Spain)
  • 2 Instituto Universitario Fernández-Vega, Universidad de Oviedo & Fundación de Investigación Oftalmológica, Oviedo, Spain. , (Spain)
  • 3 Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, 1 Illini Drive, Peoria, IL 61605, USA.
  • 4 Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, 03550 San Juan de Alicante, Spain [email protected] , (Spain)
Published Article
Journal of Neuroscience
Society for Neuroscience
Publication Date
Dec 13, 2018
DOI: 10.1523/JNEUROSCI.1726-18.2018
PMID: 30545944


TRPM8 is a polymodal, non-selective 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.Altogether, 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 STATEMENTTRPM8 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 neuro-immune 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. Copyright © 2018 the authors.

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