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 thresholds. 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 degrees C) thermal stimuli. 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 approximately 52 degrees 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.

Reduced thermal sensitivity and Nav1.8 and TRPV1 channel expression in sensory neurons of aged mice

“…TRPV1 is predominantly expressed in small, unmyelinated neurons and has a thermal activation threshold of ~43 °C [10,29,36]. The TRPV2 channel is expressed in medium and large myelinated neurons and mediates high threshold heat response with a threshold of ~52 °C [11]. TRPV3 is also heat sensitive with an activation threshold between 31 and 39 °C [34,38].…”

Temperature sensing across species

“…Subsequently, we identified a cold and menthol receptor, TRPM8, from TG neurons using a similar paradigm, thereby establishing that members of the TRP family of ion channels play an important role in thermosensation [47]. Subsequently, four additional TRP channels have been implicated in temperature sensation both in vitro and in vivo, and their properties, along with TRPV1 and TRPM8, can conceivably account for the entire spectrum of perceived temperatures [48][49][50][51][52][53][54][55] (Fig. 3).…”

“…Hence, the cloning and functional analysis of TRPV1 revealed for the first time how sensory neurons detect "moderate" threshold heat responses at the molecular level. Furthermore, several additional TRPV channels are also activated by warmth and heat, suggesting that thermosensory responses to heat are largely mediated by one class of proteins (see below) [48][49][50][52][53][54].…”

“…These channels were identified as such based upon either their sequence or structural similarity to TRPV1, expression in sensory afferents, or in vitro biophysical properties [46]. The first of these, TRPV2, is a candidate transducer of high threshold heat responses observed in medium diameter, lightly myelinated type I Aδ fibers that respond to temperatures >50°C [48,59]. In vitro, TRPV2-mediated currents are activated at a threshold temperature of 52°C, and TRPV2 expression in sensory ganglia is suggestive of expression in type I Aδ fibers [48,82].…”

“…The first of these, TRPV2, is a candidate transducer of high threshold heat responses observed in medium diameter, lightly myelinated type I Aδ fibers that respond to temperatures >50°C [48,59]. In vitro, TRPV2-mediated currents are activated at a threshold temperature of 52°C, and TRPV2 expression in sensory ganglia is suggestive of expression in type I Aδ fibers [48,82]. However, behavioral responses of TRPV2-null mice have not been reported.…”