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

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 °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 ∼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.

[1]  A. Jancsó-Gábor,et al.  Pharmacologically induced selective degeneration of chemosensitive primary sensory neurones , 1977, Nature.

[2]  A. Iggo Pain in the trigeminal region edited by D. J. Anderson and B. Matthews, Elsevier/North-Holland Biomedical Press, Amsterdam and New York, 1977. Dfl 121.00 $49.50 (xiii + 453 pages) 0 444 80011 5 , 1978, Trends in Neurosciences.

[3]  E. Perl,et al.  Reexamination of the dorsal root projection to the spinal dorsal horn including observations on the differential termination of coarse and fine fibers , 1979, The Journal of comparative neurology.

[4]  B. Anderton,et al.  Monoclonal antibodies to mammalian neurofilaments , 1981, Bioscience reports.

[5]  James N. Campbell,et al.  Primary Afferents and Hyperalgesia , 1986 .

[6]  T. Yaksh,et al.  Spinal Afferent Processing , 1986, Springer US.

[7]  J. Nathans,et al.  Molecular biology of visual pigments. , 1987, Annual review of neuroscience.

[8]  D. A. Brown,et al.  The mechanism of action of capsaicin on sensory C-type neurons and their axons in vitro , 1987, Neuroscience.

[9]  S. Bevan,et al.  Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[10]  G. Rubin,et al.  Molecular characterization of the drosophila trp locus: A putative integral membrane protein required for phototransduction , 1989, Neuron.

[11]  P. Wall,et al.  Textbook of pain , 1989 .

[12]  A. Dray,et al.  Ruthenium red blocks the capsaicin-induced increase in intracellular calcium and activation of membrane currents in sensory neurones as well as the activation of peripheral nociceptors in vitro , 1990, Neuroscience Letters.

[13]  S. Bevan,et al.  Sensory neuron-specific actions of capsaicin: mechanisms and applications. , 1990, Trends in pharmacological sciences.

[14]  H P Rang,et al.  Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin , 1992, British journal of pharmacology.

[15]  S. Bevan,et al.  Characterization of resiniferatoxin binding sites on sensory neurons: Co-regulation of resiniferatoxin binding and capsaicin sensitivity in adult rat dorsal root ganglia , 1993, Neuroscience.

[16]  R. Hardie,et al.  Novel Ca2+ channels underlying transduction in Drosophila photoreceptors: implications for phosphoinositide-mediated Ca2+ mobilization , 1993, Trends in Neurosciences.

[17]  W D Willis,et al.  Cutaneous sensory receptors in the rat foot. , 1993, Journal of neurophysiology.

[18]  D. Julius,et al.  New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor , 1994, Nature.

[19]  R. Hurst,et al.  trp, a Novel Mammalian Gene Family Essential for Agonist-Activated Capacitative Ca2+ Entry , 1996, Cell.

[20]  Cori Bargmann,et al.  OSM-9, A Novel Protein with Structural Similarity to Channels, Is Required for Olfaction, Mechanosensation, and Olfactory Adaptation inCaenorhabditis elegans , 1997, The Journal of Neuroscience.

[21]  S. Lawson,et al.  Differing action potential shapes in rat dorsal root ganglion neurones related to their substance P and calcitonin gene‐related peptide immunoreactivity , 1997, The Journal of comparative neurology.

[22]  D. Julius,et al.  The capsaicin receptor: a heat-activated ion channel in the pain pathway , 1997, Nature.

[23]  R. Hardie,et al.  In Vivo Analysis of the Drosophila Light-Sensitive Channels, TRP and TRPL , 1997, Neuron.

[24]  J. Levine,et al.  Heat transduction in rat sensory neurons by calcium-dependent activation of a cation channel. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[25]  S. McMahon,et al.  Tackling Pain at the Source: New Ideas about Nociceptors , 1998, Neuron.

[26]  A. Todd,et al.  A quantitative study of neurons which express neurokinin-1 or somatostatin sst2a receptor in rat spinal dorsal horn , 1998, Neuroscience.

[27]  A. Basbaum,et al.  The Cloned Capsaicin Receptor Integrates Multiple Pain-Producing Stimuli , 1998, Neuron.

[28]  P. McIntyre,et al.  Capsaicin sensitivity is associated with the expression of the vanilloid (capsaicin) receptor (VR1) mRNA in adult rat sensory ganglia , 1998, Neuroscience Letters.

[29]  C. Zuker,et al.  TRP, TRPL and trouble in photoreceptor cells , 1998, Current Opinion in Neurobiology.

[30]  I. Nagy,et al.  Noxious heat activates all capsaicin-sensitive and also a sub-population of capsaicin-insensitive dorsal root ganglion neurons , 1999, Neuroscience.