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All data are available from the corresponding author upon reasonable request.
References
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Acknowledgements
We thank T. Buijs for discussions. This work was supported by Wellcome Trust Investigator Award grant 205006/Z/16/Z to P.A.M. and by grants from the Ministry of Science and Technology, Taipei, Taiwan (MOST 106-2314-B-037-097-MY2 and MOST 108-2320-B-037-034-MY3) to C.-H.T.
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All authors planned the study and co-wrote the manuscript. B.V. carried out all experimental work except that presented in Extended Data Fig. 1a, which was carried out by C.-H.T.
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Extended data figures and tables
Extended Data Fig. 1 Changing the source of neurons, the order of application of agonists and the heat stimulus, the culture conditions, the rise time of heat application and the starting temperature do not significantly affect the proportions of heat-sensitive neurons with responses that are not attributable to TRPV1, TRPM3 or TRPA1 .
a, Neurons from the TG were tested for heat and agonist sensitivity. Left, percentage distributions of heat-sensitive and agonist-sensitive neurons. TRPA1 is strongly co-expressed with TRPV1 or TRPM3 (39%), with few neurons expressing TRPA1 alone (2.5%). Heat-sensitive neurons that respond to heat but do not express any of TRPV1, TRPM3 or TRPA1 can be clearly identified (8%). n = 388 neurons from 1 wild-type mouse. Right, similar experiment on n = 382 TG neurons from 1 Trpm2−/− mouse. The proportion of heat-sensitive neurons with responses that are not attributable to TRPV1, TRPM3 or TRPA1 is significantly reduced compared with the wild type (from 8% to 3%, P = 0.0077, Fisher’s exact test). The mean response amplitude of heat-sensitive neurons with responses that are not attributable to TRPV1, TRPM3 or TRPA1 was not significantly reduced by deletion of Trpm2 (ΔF340/F380 = 1.13 ± 0.05, n = 31 for wild type to 0.96 ± 0.08, n = 13 for Trpm2−/−, difference not significant, P = 0.0539, unpaired t-test). b, Neurons from the DRG were tested for heat and agonist sensitivity using the protocol shown in Fig. 2a, but without the application of 2-APB and with agonists presented after heat rather than before. Left, neurons were cultured for 12 h in NGF1. See Methods for details. The pie chart shows data from 3 experiments on a total of 1,312 neurons from 3 wild-type mice on 12 coverslips as follows: neurons expressing only TRPV1 (32.2 ± 4.2%, mean ± s.e.m.); only TRPM3 (8.2 ± 1.2%); both TRPV1 and TRPM3 but not TRPA1 (13.3 ± 0.6%); TRPA1 together with either TRPV1 or TRPM3 (13.3 ± 0.9%); TRPA1 alone and responding to heat (0.2 ± 0.2%); TRPA1 alone and not responding to heat (0.4 ± 0.2%); heat-sensitive neurons responding to heat but not to agonists for any of TRPV1, TRPM3 or TRPA1 (7.6 ± 2.0%); and neurons not responding to heat nor to any of the TRP agonists but that were identified as viable from their response to a final pulse of KCl (24.8 ± 1.8%). The application of agonists before (Fig. 1a) or after the heat pulse (this Figure) does not significantly affect the proportion of heat-sensitive neurons with responses that are not attributable to TRPV1, TRPM3 or TRPA1 (9.5 ± 0.2% when agonists are applied before (Fig. 1a) and 7.6 ± 2.0% when applied after, P = 0.3740, unpaired t-test). The proportions of neurons in other categories are also not significantly affected, apart from a small reduction in the proportion of neurons expressing TRPA1 in combination with TRPV1 and/or TRPM3 (compare with Fig. 1a). Right, neurons cultured for 12 h in medium containing glial cell line-derived neurotrophic factor (GDNF) at 2 ng ml−1 and neurotrophin 4 (NT4) at 10 ng ml−1, the same culture protocol used by Vandewauw et al.2. n = 1,521 neurons from 3 wild-type mice on 12 coverslips. The altered culture conditions had no significant effect on the proportions of heat-sensitive and agonist-sensitive neurons (P > 0.05, multiple t-test with Bonferroni correction). c, Left, protocols for determining the total proportion of DRG neurons in which heat responses are partly driven by a mechanism independent of TRPV1, TRPM3 or TRPA1. The heat ramp is first applied in a Ca-free solution, to identify changes in the F340/F380 fluorescence ratio (ΔF340/F380) arising from sensitivity of the fura2 dye to temperature, followed by an identical ramp in the presence of a cocktail of inhibitors of TRPV1 (AMG9810, 5 μM), TRPM3 (naringenin, 10 μM) and TRPA1 (HC-030031, 100 μM) (see details in Methods). A final pulse of KCl confirms viability of the neurons. Right, top: heat application in which the temperature was increased from 33 °C to 48 °C over 180 s (ref. 1). n = 710 neurons from 2 wild-type mice on 3 coverslips. Middle, heat application in which the temperature was increased from 33 °C to 48 °C over 25 s (ref. 2). n = 99 neurons from 1 wild-type mouse on 2 coverslips. Bottom, heat application in which the temperature was increased from 23 °C to 48 °C over 180 s (ref. 2). n = 657 neurons from 1 wild-type mouse on 2 coverslips. Reducing the rise time of heat application or the starting temperature does not reduce the total proportion of heat-sensitive neurons with responses that are not attributable to TRPV1, TRPM3 or TRPA1. Differences not significant, P = 0.9197 (middle) and 0.3339 (bottom) respectively, unpaired t-test compared to top panel.
Extended Data Fig. 2 Effect of TRPM2 blocker 2-APB on heat responses in neurons expressing only one of TRPA1, TRPV1 or TPRPM3.
Neurons were identified as expressing only one of TRPA1 (left), TRPV1 (middle) or TRPM3 (right) and the effect of 2-APB (25 μM) was tested as shown in Fig. 2a. a, Wild-type neurons. Note that many of these neurons will co-express TRPM2, which is extensively expressed in somatosensory neurons (Fig. 1c). b, Similar experiments on Trpm2−/− neurons. Significance level during 2-APB application compared to that after wash is as follows: *P < 0.05; **P < 0.01; ***P < 0.001; NS, P > 0.05. One-way ANOVA followed by Bonferroni's post hoc correction.
Extended Data Fig. 3 A fraction of TRPA1+ neurons from Trpm2−/− mice responds to heat when TRPV1 and TRPM3 are blocked.
a, Top trace shows protocol of solution changes used to identify neurons expressing TRPA1 and to test their activation by heat. TRPV1 and TRPM3 were blocked by AMG9810 (5 μM) and naringenin (10 μM) as shown. The calcium increase elicited by a heat ramp from 33 °C to 48 °C was tested in the absence (heat ramps 1 and 3) and the presence (ramp 2) of the TRPA1 blocker HC030031 (100 μM). Responses to the TRPA1-selective agonist AITC were tested as shown. The response to KCl (50 mM) and to the heat ramp in the absence of external Ca was tested at the end. Middle trace shows increases in F340/380 in a neuron expressing TRPA1 in which the heat-activated Ca increase was suppressed by the TRPA1 blocker HC030031. TRPA1 was expressed in 31.2 ± 4.2% of the total population, but only a fraction of TRPA1+ neurons (34.7% ± 9.81%) gave a significant Ca increase in response to 48 °C heat. Lower trace shows a different neuron in same preparation that is activated by heat but does not express TRPA1 (unidentified heat-responders). Representative data from 3 separate experiments on a total of 964 neurons. b, Heat response in TRPA1-expressing neurons is suppressed by the TRPA1 blocker HC030031 (see a for protocol (top) and example trace (middle)). ***P < 0.001, one-way ANOVA followed by Bonferroni's post hoc correction. c, Heat response in neurons not expressing TRPA1 (unidentified heat-responsive neurons, see a for example trace (bottom)) is not significantly reduced by the TRPA1 blocker HC030031 (100 μM). The proportion of unidentified heat-responders (5.5% ± 1.4%) is not significantly different from that in Fig. 1d.
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Vilar, B., Tan, CH. & McNaughton, P.A. Heat detection by the TRPM2 ion channel. Nature 584, E5–E12 (2020). https://doi.org/10.1038/s41586-020-2510-7
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DOI: https://doi.org/10.1038/s41586-020-2510-7
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