Identification of a cold receptor reveals a general role for TRP channels in thermosensation

McKemy, David D.; Neuhausser, Werner M.; Julius, David

doi:10.1038/nature719

Cited by 2,339 publications

(2,337 citation statements)

References 46 publications

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“…All three are specifically expressed in TrkA-positive DRG neurons in newborn mice [13][14][15] . The expression of these TrkA-specific genes was not detectable in TrkA TrkC/TrkC mice or in TrkA τlacZ/τlacZ mice ( Fig.…”

Section: The Rescued Neurons Adopt a Proprioceptive Phenotypementioning

confidence: 99%

Expressing TrkC from the TrkA locus causes a subset of dorsal root ganglia neurons to switch fate

et al. 2004

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Tactile information is perceived by a heterogeneous population of specialized neurons. Neurotrophin receptors (the receptor tyrosine kinases, Trks) mark the major classes of these sensory neurons: TrkA is expressed in neurons that sense temperature and noxious stimuli, and TrkC is expressed in proprioceptive neurons that sense body position. Neurotrophin signaling through these receptors is required for cell survival. To test whether neurotrophins have an instructive role in sensory specification, we expressed rat TrkC from the TrkA (also known as Ntrk1) locus in mice. The surviving presumptive TrkA-expressing neurons adopted a proprioceptive phenotype, indicating that neurotrophin signaling can specify sensory neuron subtypes.Neurotrophins are well-characterized growth factors required for the survival of developing sensory neurons by signaling through a class of receptor tyrosine kinases 1-3 . The Trk receptors are specifically expressed in functionally distinct neurons of the dorsal root ganglia (DRG). TrkA, the receptor for nerve growth factor (NGF) is expressed in nociceptive and thermoceptive sensory neurons; TrkC, the high-affinity receptor for neurotrophin-3 (NT-3), is expressed in proprioceptive neurons; and TrkB, the receptor for brain-derived neurotrophic factor (BDNF) and NT-4, is expressed in less specifically characterized touch neurons. Each Trk receptor is required for the survival of the distinct class of neurons that it marks, consistent with a permissive role of neurotrophin signaling in neuronal survival. Various studies have suggested that Trk signaling is also involved in instructive steps of DRG development 4 . For example, neurotrophins are able to guide DRG axons in culture, and Bax -/-; TrkA -/-or Bax -/-;NT3 -/-DRG neurons, which are rescued from apoptosis by the lack of functional Bax protein, fail to develop properly 5-10 . To directly test whether signaling by a specific Trk can specify the subtype of DRG neurons in vivo, we designed a knock-in construct that expresses rat TrkC protein from the mouse TrkA locus while inactivating native TrkA expression. Table 2 and Fig. 4e-h).To further demonstrate that an effect on survival of existing proprioceptive neurons cannot account for the phenotype observed in TrkA TrkC/TrkC mice, we crossed the knock-in mice to Bax -/-mice. The deletion of Bax rescues DRG neurons from apoptosis, but does not cause the formation of extra proprioceptive neurons, as judged by the number of muscle spindles 10 (also compare parvalbumin and spindle counts in wild-type and Bax -/-mice; Tables 1 and 2). Notably, we observed a five-fold increase in parvalbumin-positive L5 DRGs and a seven-fold increase in muscle spindles in the soleus muscle of TrkA TrkC/TrkC ;Bax -/-mice when compared to Bax -/-mice ( Functional endogenous TrkC is required for the phenotypic switchIn an attempt to visualize the projection patterns of the ectopic proprioceptive neurons, we analyzed TrkA τlacZ/TrkC compound heterozygous mice. The TrkA-positive DRG neuronal projections are...

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Section: The Rescued Neurons Adopt a Proprioceptive Phenotypementioning

confidence: 99%

Expressing TrkC from the TrkA locus causes a subset of dorsal root ganglia neurons to switch fate

et al. 2004

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“…Indeed, they hypothesized that menthol exerts its actions upon "an enzyme" that is involved in the activation of these nerves [70]. Similar responses are observed in cultured neurons with both menthol and cold evoking rapidly activating, nonselective cation conductances in a temperature-dependent manner [47,71]. Both mentholand cold-evoked currents also adapt to prolonged stimulation at a rate that is similar to what is observed in primates and humans [72].…”

Section: The Hot Of Capsaicin and The Cool Of Mentholmentioning

confidence: 75%

“…This hypothesis was first validated when Caterina et al [25] cloned the capsaicin receptor, TRPV1, from DRG neurons and established that this ion channel is activated by noxious heat in vitro. 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.…”

Section: Vertebrate Thermosensory Mechanismsmentioning

confidence: 90%

Temperature sensing across species

McKemy

2007

Pflugers Arch - Eur J Physiol

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The ability to detect changes in temperature is a fundamental sensory mechanism for every species and provides organisms with a detailed view of the environment. This review focuses on what is known of the neuronal and molecular substrates for thermosensation across species, focusing on the three robust model systems extensively used to study sensory signaling, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the laboratory mouse. Nematodes migrate to thermal climes that are amenable to their survival, a behavior that is regulated primarily through a single sensory neuron. Additionally, nematodes "learn" to seek out this temperate zone based upon their prior experience, a robust model of learning and memory. Drosophila larvae also prefer select thermal zones that are optimal for growth and have also developed vigorous mechanisms to avoid unfavorable conditions. In mammals, the transduction mechanisms for thermosensation have been identified primarily due to the fact that naturally occurring plant products evoke distinct psychophysical sensation of temperature change. More remarkably, the elucidation of the molecular sensors in mammals, along with those in Drosophila, has demonstrated conservation in the molecular mediators of temperature sensation across diverse species.

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“…Icilin is a cold-inducing agent that activates two transient receptor potential channels, TRPM8 and TRPA1, in the dorsal root ganglia and trigeminal neurons of the periphery (McKemy et al, 2002;Peier et al, 2002;Reid et al, 2002;Story et al, 2003;Bandell et al, 2004;Jordt et al, 2004;Liu et al, 2006). Upon application to the skin or on the tongue, icilin produces "mild, pleasant sensations of coolness, similar to menthol but discrete and non-irritating" and is 400-600 times more potent than menthol (Wei and Seid, 1983;Behrendt et al,2004;Wei, 2005).Icilin may potentially be used in the treatment of pruritus, hemorrhoids, canker sores, arthritis and pain (Wei and Seid, 1983;Wei, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…TRPM8 is activated by cool temperatures (<25°C), menthol and icilin (McKemy et al, 2002;Peier et al, 2002); whereas TRPA1 is activated by noxious cold (<17°C), icilin, pungent natural compounds (mustard oil, wintergreen oil, clove oil, cinnamon oil, ginger oil) (Bandell et al, 2004), and raw garlic (Bandell et al, 2004;Bautista et al, 2005;Macpherson et al, 2005), but not by menthol (Story et al, 2003;Jordt et al, 2004). Activation of these channels by their respective agonists results in calcium ion influx and desensitization (McKemy et al, 2002;Peier et al, 2002;Story et al, 2003;Jordt et al, 2004;Liu et al, 2006). Investigation of the downstream effect of channel activation remains unclear, supporting the need to investigate the pharmacology of cold-inducing compounds in vivo.…”

Section: Introductionmentioning

confidence: 99%

Nalfurafine, the kappa opioid agonist, inhibits icilin-induced wet-dog shakes in rats and antagonizes glutamate release in the dorsal striatum

Werkheiser¹,

Cowan²

2007

Neuropharmacology

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Icilin, a cooling compound, produces vigorous wet-dog shakes in rats. We have reported previously that icilin-induced wet-dog shakes are blocked by the kappa opioid receptor agonists, nalfurafine and U50,488H, and that icilin evokes a dose-and time-dependent increase in glutamate within the dorsal striatum. Since activation of kappa opioid receptors inhibits glutamate release intrastriatally, we targeted glutamate release within the dorsal striatum using nalfurafine and examined the role of the dorsal striatum in icilin-induced wet-dog shakes, more specifically, the effect that icilin-evoked intrastriatal glutamate release has on the overt stimulant behavior. We report that nalfurafine (0.04 mg/kg) inhibits icilin (0.50 mg/kg)-induced wet-dog shakes and that this inhibition is reversed by intrastriatal perfusion of the kappa opioid receptor antagonist, norbinaltorphimine (100 nM). Furthermore, we antagonized icilin-evoked glutamate release with nalfurafine (0.04 mg/kg), and reversed inhibition of glutamate release with intrastriatal norbinaltorphimine (100 nM). These findings support a central component in the behavioral response to icilin and suggest that activation of kappa opioid receptors antagonizes icilin-induced wet-dog shakes in rats by inhibiting glutamate release within the dorsal striatum.

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Identification of a cold receptor reveals a general role for TRP channels in thermosensation

Cited by 2,339 publications

References 46 publications

Expressing TrkC from the TrkA locus causes a subset of dorsal root ganglia neurons to switch fate

Expressing TrkC from the TrkA locus causes a subset of dorsal root ganglia neurons to switch fate

Temperature sensing across species

Nalfurafine, the kappa opioid agonist, inhibits icilin-induced wet-dog shakes in rats and antagonizes glutamate release in the dorsal striatum

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