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The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels

Abstract

The mammalian sensory system is capable of discriminating thermal stimuli ranging from noxious cold to noxious heat. Principal temperature sensors belong to the TRP cation channel family, but the mechanisms underlying the marked temperature sensitivity of opening and closing (‘gating’) of these channels are unknown. Here we show that temperature sensing is tightly linked to voltage-dependent gating in the cold-sensitive channel TRPM8 and the heat-sensitive channel TRPV1. Both channels are activated upon depolarization, and changes in temperature result in graded shifts of their voltage-dependent activation curves. The chemical agonists menthol (TRPM8) and capsaicin (TRPV1) function as gating modifiers, shifting activation curves towards physiological membrane potentials. Kinetic analysis of gating at different temperatures indicates that temperature sensitivity in TRPM8 and TRPV1 arises from a tenfold difference in the activation energies associated with voltage-dependent opening and closing. Our results suggest a simple unifying principle that explains both cold and heat sensitivity in TRP channels.

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Figure 1: Outward rectification of TRPM8 is due to voltage-dependent gating.
Figure 2: Cooling activates TRPM8 by shifting the voltage dependence of activation.
Figure 3: Heating activates TRPV1 by shifting the voltage dependence of activation.
Figure 4: A two-state model accurately predicts the temperature-dependent behaviour of TRPM8 and TRPV1.
Figure 5: Menthol shifts the TRPM8 activation curve.
Figure 6: Capsaicin shifts the TRPV1 activation curve.

References

  1. Julius, D. & Basbaum, A. I. Molecular mechanisms of nociception. Nature 413, 203–210 (2001)

    Article  ADS  CAS  Google Scholar 

  2. Patapoutian, A., Peier, A. M., Story, G. M. & Viswanath, V. ThermoTRP channels and beyond: mechanisms of temperature sensation. Nature Rev. Neurosci. 4, 529–539 (2003)

    Article  CAS  Google Scholar 

  3. Clapham, D. E. TRP channels as cellular sensors. Nature 426, 517–524 (2003)

    Article  ADS  CAS  Google Scholar 

  4. Voets, T. & Nilius, B. TRPs make sense. J. Membr. Biol. 192, 1–8 (2003)

    Article  CAS  Google Scholar 

  5. Watanabe, H. et al. Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells. J. Biol. Chem. 277, 47044–47051 (2002)

    Article  CAS  Google Scholar 

  6. Güler, A. D. et al. Heat-evoked activation of the ion channel, TRPV4. J. Neurosci. 22, 6408–6414 (2002)

    Article  Google Scholar 

  7. Xu, H. et al. TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature 418, 181–186 (2002)

    Article  ADS  CAS  Google Scholar 

  8. Smith, G. D. et al. TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature 418, 186–190 (2002)

    Article  ADS  CAS  Google Scholar 

  9. Peier, A. M. et al. A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046–2049 (2002)

    Article  ADS  CAS  Google Scholar 

  10. Caterina, M. J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997)

    Article  ADS  CAS  Google Scholar 

  11. Caterina, M. J., Rosen, T. A., Tominaga, M., Brake, A. J. & Julius, D. A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398, 436–441 (1999)

    Article  ADS  CAS  Google Scholar 

  12. McKemy, D. D., Neuhäusser, W. M. & Julius, D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416, 52–58 (2002)

    Article  ADS  CAS  Google Scholar 

  13. Peier, A. M. et al. A TRP channel that senses cold stimuli and menthol. Cell 108, 705–715 (2002)

    Article  CAS  Google Scholar 

  14. Story, G. M. et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819–829 (2003)

    Article  CAS  Google Scholar 

  15. Jordt, S. E. et al. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427, 260–265 (2004)

    Article  ADS  CAS  Google Scholar 

  16. Hille, B. Ion channels of Excitable Membranes (Sinauer Associates, Sunderland, Massachusetts, 2001)

    Google Scholar 

  17. Launay, P. et al. TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell 109, 397–407 (2002)

    Article  CAS  Google Scholar 

  18. Nilius, B. et al. Voltage dependence of the Ca2+-activated cation channel TRPM4. J. Biol. Chem. 278, 30813–30820 (2003)

    Article  CAS  Google Scholar 

  19. Hofmann, T., Chubanov, V., Gudermann, T. & Montell, C. TRPM5 is a voltage-modulated and Ca2+-activated monovalent selective cation channel. Curr. Biol. 13, 1153–1158 (2003)

    Article  CAS  Google Scholar 

  20. Gunthorpe, M. J., Harries, M. H., Prinjha, R. K., Davis, J. B. & Randall, A. Voltage- and time-dependent properties of the recombinant rat vanilloid receptor (rVR1). J. Physiol. (Lond.) 525, 747–759 (2000)

    Article  CAS  Google Scholar 

  21. Vlachova, V. et al. Functional role of C-terminal cytoplasmic tail of rat vanilloid receptor 1. J. Neurosci. 23, 1340–1350 (2003)

    Article  CAS  Google Scholar 

  22. Tominaga, M. et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21, 531–543 (1998)

    Article  CAS  Google Scholar 

  23. Marsh, D. General features of phospholipid phase transitions. Chem. Phys. Lipids 57, 109–120 (1991)

    Article  CAS  Google Scholar 

  24. Sigworth, F. J. Voltage gating of ion channels. Q. Rev. Biophys. 27, 1–40 (1994)

    Article  CAS  Google Scholar 

  25. Tiwari, J. K. & Sikdar, S. K. Temperature-dependent conformational changes in a voltage-gated potassium channel. Eur. Biophys. J. 28, 338–345 (1999)

    Article  CAS  Google Scholar 

  26. van Lunteren, E., Elmslie, K. S. & Jones, S. W. Effects of temperature on calcium current of bullfrog sympathetic neurons. J. Physiol. (Lond.) 466, 81–93 (1993)

    CAS  Google Scholar 

  27. Chung, M. K., Lee, H. & Caterina, M. J. Warm temperatures activate TRPV4 in mouse 308 keratinocytes. J. Biol. Chem. 278, 32037–32046 (2003)

    Article  CAS  Google Scholar 

  28. Liu, B., Hui, K. & Qin, F. Thermodynamics of heat activation of single capsaicin ion channels VR1. Biophys. J. 85, 2988–3006 (2003)

    Article  ADS  CAS  Google Scholar 

  29. Jordt, S. E., Tominaga, M. & Julius, D. Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc. Natl Acad. Sci. USA 97, 8134–8139 (2000)

    Article  ADS  CAS  Google Scholar 

  30. Zygmunt, P. M. et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457 (1999)

    Article  ADS  CAS  Google Scholar 

  31. Behrendt, H. J., Germann, T., Gillen, C., Hatt, H. & Jostock, R. Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay. Br. J. Pharmacol. 141, 737–745 (2004)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Talavera, G. Owsianik, J. Vriens, F. Mahieu and J. Prenen for helpful suggestions and criticisms, and C. Benham (GlaxoSmithKline) for providing us with the human TRPV1 clone. This work was supported by the Belgian Federal Government, the Flemish Government and the Onderzoeksraad KU Leuven. T.V. is a postdoctoral Fellow of the Fund for Scientific Research, Flanders (Belgium) (FWO-Vlaanderen).

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Supplementary information

Supplementary Figure

This figure shows examples of the detailed kinetic analysis of current relaxations for TRPM8 and TRPV1 at different temperatures and voltages. (DOC 101 kb)

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Voets, T., Droogmans, G., Wissenbach, U. et al. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 430, 748–754 (2004). https://doi.org/10.1038/nature02732

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