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. 2009 May 6;28(9):1308-18.
doi: 10.1038/emboj.2009.57. Epub 2009 Mar 12.

The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception

Jacques Noël  1 , Katharina Zimmermann, Jérome Busserolles, Emanuel Deval, Abdelkrim Alloui, Sylvie Diochot, Nicolas Guy, Marc Borsotto, Peter Reeh, Alain Eschalier, Michel Lazdunski
Affiliations

The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception

Jacques Noël et al. EMBO J. .

Abstract

The sensation of cold or heat depends on the activation of specific nerve endings in the skin. This involves heat- and cold-sensitive excitatory transient receptor potential (TRP) channels. However, we show here that the mechano-gated and highly temperature-sensitive potassium channels of the TREK/TRAAK family, which normally work as silencers of the excitatory channels, are also implicated. They are important for the definition of temperature thresholds and temperature ranges in which excitation of nociceptor takes place and for the intensity of excitation when it occurs. They are expressed with thermo-TRP channels in sensory neurons. TRAAK and TREK-1 channels control pain produced by mechanical stimulation and both heat and cold pain perception in mice. Expression of TRAAK alone or in association with TREK-1 controls heat responses of both capsaicin-sensitive and capsaicin-insensitive sensory neurons. Together TREK-1 and TRAAK channels are important regulators of nociceptor activation by cold, particularly in the nociceptor population that is not activated by menthol.

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Figures

Figure 1
Figure 1
Mechanical allodynia in TRAAK−/− and TREK1−/−-TRAAK−/− mice. (A) Mechanical sensitivity was measured on mice of indicated genotypes with paw withdrawal thresholds to von Frey hairs of increasing stiffness. (B) Intradermal injection of hypertonic saline (NaCl 2%) caused moderate nociceptive behaviour in wild-type, TRAAK−/− and TREK1−/−-TRAAK−/− mice. Sensitization with PGE2 (5 μM) potentiated the hypertonicity-induced nociceptive behaviour in wild-type and TRAAK−/− mice, but was not effective in the TREK1−/−-TRAAK−/− mice. Values are mean±s.e.m. NS: not significant. Stars mark significant difference, with one star for P<0.05 and three stars for P<0.001; ANOVA with Tuckey's post-test.
Figure 2
Figure 2
Enhanced heat sensitivity of TRAAK−/−, TREK1−/− and TREK1−/−-TRAAK−/− DRG neurons and C-fibres. (A) Fractions of heat (∼48°C)-sensitive DRG neurons cultured from wild-type (338 neurons, 19 separate measures), TRAAK−/− (182 neurons, 16 separate measures), TREK-1−/− (200 neurons, 13 separate measures) and TREK-1−/−-TRAAK−/− mice (80 neurons, 8 separate measures). Light grey shows the fractions of heat-sensitive capsaicin-insensitive neurons. Dark grey shows the fractions of heat- and capsaicin-sensitive neurons. (B) Proportions of heat-sensitive C-fibres in wild-type (n=78), TRAAK−/− (n=40), TREK-1−/− (n=41) and TREK1−/−-TRAAK−/− (n=75) mice measured in nerve-skin experiments. (C) Top: a representative experiment from a TREK1−/−-TRAAK−/− C-fibre with its frequency plot, showing action potentials (Spikes) in response to the noxious heat ramp shown below. The average action potential is presented on the right. Bottom: histogram of averaged heat responses of wild-type, TRAAK−/− and TREK1−/−-TRAAK−/− C-fibres. Values are mean±s.e.m. One star marks P<0.05 over wild type; χ2 test.
Figure 3
Figure 3
Heat hyperalgesia of TRAAK−/− and TREK-1−/−-TRAAK−/− mice in normal and pathological conditions. (A) Tail immersion test at increasing bath temperatures on wild-type, TRAAK−/− and TREK-1−/−-TRAAK−/− mice. (B) Measures of heat hyperalgesia of the paw before (time 0) and at 24 h of carrageenan-induced inflammation of the paw. The inflamed paw was immersed in a bath at 46°C. (C) Measures of heat hyperalgesia of the paw in a bath at 46°C before (time 0) and 12 days after chronic constriction of the sciatic nerve in wild-type, TRAAK−/− and TREK-1−/−-TRAAK−/− mice. Values are mean±s.e.m. Stars mark significant difference with P<0.05 for one star and P<0.01 for two stars. Two-way ANOVA, Tukey's post-test.
Figure 4
Figure 4
Cold sensitivity of DRG neurons and C-fibres of TRAAK−/− and TREK1−/−-TRAAK−/− mice. (A) Proportions of cultured DRG neurons sensitive to cooling between 30 and 12°C, from wild-type, TRAAK−/−, TREK-1−/− and TREK-1−/−-TRAAK−/− mice. Fractions are shown of cold- and menthol-sensitive neurons (light grey) and cold-sensitive and menthol-insensitive neurons (white). Two stars for P<0.01; χ2 test. (B) Proportion of cold-sensitive C-fibres in the skin of wild-type (n=78), TRAAK−/− (n=40), TREK-1−/− (n=41) and TREK-1−/−-TRAAK−/− mice (n=75). The star for P<0.05; χ2 test. (C) A representative response of a TREK1−/−-TRAAK−/− C-fibre to a cold stimulus with its frequency plot. Action potentials (spikes) are shown with their average. Bottom: average histogram (4 s bin, mean±s.e.m.) of wild-type (white-bar) and TREK1−/−-TRAAK−/− (dark bars) C-fibre responses to a 60 s cooling pulse from 30 to 10°C, shown above. (D) Relative frequency distribution plot of wild-type and TREK1−/−-TRAAK−/− C-fibre response to cold. Class interval 5 spikes. (E) Relative frequency distribution plot of cold thresholds of C-fibres from wild-type and TREK1−/−-TRAAK−/− mice. Class interval 2°C.
Figure 5
Figure 5
Cold-sensitive behaviour of wild-type, TRAAK−/− and TREK-1−/−-TRAAK−/− mice in normal and CCI neurophatic conditions. (A) Nocifensive cold-plate test showing reduced latency of TREK-1−/−-TRAAK−/− mice. The temperature of the plate is indicated in the graph. (B) Thermal discrimination test with two temperature plates. The temperature of one of the plates was maintained at 30°C and the temperature of the second plate was set as indicated. The time indicated is the fraction of time spent by the mice on the 30°C plate measured over 3 min. (C) Cold allodynia of CCI neuropathic wild-type, TRAAK−/− and TREK-1−/−-TRAAK−/− mice measured as the total time of lifting of the paw over 3 min when mice were placed on a cold plate at 15 and 20°C. Values are mean±s.e.m. Stars mark significant differences, with one star for P<0.05 and two stars for P<0.01; two-way ANOVA with Tukey's post-test.
Figure 6
Figure 6
Mechano- and thermo-sensitive TREK-1 and TRAAK channels work in concert with and oppose depolarization induced by mechano-and thermo-sensitive excitatory channels in nociceptors. (A) Membrane stretch opens TREK-1 and TRAAK hyperpolarizing channels. Above a noxious and potentially tissue-damaging threshold, mechano-activated depolarizing channels dominate TREK-1 and TRAAK channels to activate nociceptive neurons and produce pain. (B) At tempered skin temperatures, temperature-sensitive TREK-1 and TRAAK channels are opened, they hyperpolarize the plasma membrane and impose an inactivation of nociceptive neurons. Both noxious heat and noxious cold temperatures cause the progressive decline of the hyperpolarizing contribution of TREK-1 and TRAAK channels in front of the steep activation of warm-sensitive and cold-sensitive depolarizing channels. Excitatory channels can work in association either with TREK-1 or TRAAK channels alone or with the combination of the two K2P channels. Thermal thresholds of pain (dashed line) in the warm or cold direction will depend on the type of associations between excitatory channels (most probably thermo-TRP channels) and the TREK-1 and TRAAK channels.
See this image and copyright information in PMC

Comment in

  • TREKing noxious thermosensation.
    Pongs O. Pongs O. EMBO J. 2009 May 6;28(9):1195-6. doi: 10.1038/emboj.2009.107. EMBO J. 2009. PMID: 19421163 Free PMC article. No abstract available.

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