A capsaicin-receptor homologue with a high threshold for noxious heat

Abstract

Pain-producing heat is detected by several classes of nociceptive sensory neuron that differ in their thermal response thresholds1,2,3. The cloned capsaicin receptor, also known as the vanilloid receptor subtype 1 (VR1), is a heat-gated ion channel that has been proposed to mediate responses of small-diameter sensory neurons to moderate (43 °C) thermal stimuli4,5. VR1 is also activated by protons, indicating that it may participate in the detection of noxious thermal and chemical stimuli in vivo. Here we identify a structurally related receptor, VRL-1, that does not respond to capsaicin, acid or moderate heat. Instead, VRL-1 is activated by high temperatures, with a threshold of 52 °C. Within sensory ganglia, VRL-1 is most prominently expressed by a subset of medium- to large-diameter neurons, making it a candidate receptor for transducing high-threshold heat responses in this class of cells. VRL-1 transcripts are not restricted to the sensory nervous system, indicating that this channel may be activated by stimuli other than heat. We propose that responses to noxious heat involve these related, but distinct, ion-channel subtypes that together detect a range of stimulus intensities.

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Figure 1: Alignment of cDNA sequences of rat VRL-1, human VRL-1 and rat VR1.
Figure 2: VRL-1 is activated by heat, but not by vanilloids or protons.
Figure 3: VRL-1 exhibits a higher activation threshold than VR1.
Figure 4: VRL-1 is highly expressed in a subset of medium- to large-diameter sensory neurons.
Figure 5: VR1 and VRL-1 proteins show distinct expression patterns among DRG neurons of different size classes.

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Acknowledgements

We thank M. Bland for assistance with immunolocalization; L. England, J. Onuffer and members of the Basbaum laboratory for advice regarding primary neuronal culture, immunolocalization, and affinity purification methods; and A. Basbaum, H. Chuang, L. England, H. Ingraham and S.Jordt for comments on the manuscript. M.J.C. is an American Cancer Society postdoctoral fellow and NARSAD young investigator; M.T. is a Comroe Fellow of the UCSF Cardiovascular Research Institute. This work was supported by grants from NIGMS and NIDR.

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Correspondence to David Julius.

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Caterina, M., Rosen, T., Tominaga, M. et al. A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398, 436–441 (1999). https://doi.org/10.1038/18906

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