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Specific roles for DEG/ENaC and TRP channels in touch and thermosensation in C. elegans nociceptors

Nature Neuroscience volume 13, pages 861–868 (2010)Cite this article

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Abstract

Polymodal nociceptors detect noxious stimuli, including harsh touch, toxic chemicals and extremes of heat and cold. The molecular mechanisms by which nociceptors are able to sense multiple qualitatively distinct stimuli are not well understood. We found that the C. elegans PVD neurons are mulitidendritic nociceptors that respond to harsh touch and cold temperatures. The harsh touch modality specifically required the DEG/ENaC proteins MEC-10 and DEGT-1, which represent putative components of a harsh touch mechanotransduction complex. In contrast, responses to cold required the TRPA-1 channel and were MEC-10 and DEGT-1 independent. Heterologous expression of C. elegans TRPA-1 conferred cold responsiveness to other C. elegans neurons and to mammalian cells, indicating that TRPA-1 is a cold sensor. Our results suggest that C. elegans nociceptors respond to thermal and mechanical stimuli using distinct sets of molecules and identify DEG/ENaC channels as potential receptors for mechanical pain.

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Figure 1: PVD neurons respond to harsh touch and cold temperature.
Figure 2: mec-10 is required for harsh touch in PVD.
Figure 3: DEGT-1 is required for harsh touch responses in PVD.
Figure 4: Localization patterns of DEGT-1 and MEC-10 fusion proteins in PVD.
Figure 5: Effect of mec-10 on harsh touch responses in ALM.
Figure 6: TRPA-1 is specifically required for cold responses in PVD.
Figure 7: Heterologous expression of TRPA-1 in C. elegans neurons confers cold sensitivity.
Figure 8: Cold stimuli activate TRPA-1–expressing HEK293T cells.

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References

  1. Patapoutian, A., Tate, S. & Woolf, C.J. Transient receptor potential channels: targeting pain at the source. Nat. Rev. Drug Discov. 8, 55–68 (2009).

    Article  CAS  Google Scholar 

  2. Wemmie, J.A., Price, M.P. & Welsh, M.J. Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci. 29, 578–586 (2006).

    Article  CAS  Google Scholar 

  3. Caterina, M.J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997).

    Article  CAS  Google Scholar 

  4. Tominaga, M. et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21, 531–543 (1998).

    Article  CAS  Google Scholar 

  5. McKemy, D.D., Neuhausser, W.M. & Julius, D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416, 52–58 (2002).

    Article  CAS  Google Scholar 

  6. Peier, A.M. et al. A TRP channel that senses cold stimuli and menthol. Cell 108, 705–715 (2002).

    Article  CAS  Google Scholar 

  7. Story, G.M. et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819–829 (2003).

    Article  CAS  Google Scholar 

  8. Bandell, M. et al. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41, 849–857 (2004).

    Article  CAS  Google Scholar 

  9. Bautista, D.M. et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124, 1269–1282 (2006).

    Article  CAS  Google Scholar 

  10. Christensen, A.P. & Corey, D.P. TRP channels in mechanosensation: direct or indirect activation? Nat. Rev. Neurosci. 8, 510–521 (2007).

    Article  CAS  Google Scholar 

  11. Kahn-Kirby, A.H. & Bargmann, C.I. TRP channels in C. elegans. Annu. Rev. Physiol. 68, 719–736 (2006).

    Article  CAS  Google Scholar 

  12. Kang, K. et al. Analysis of Drosophila TRPA1 reveals an ancient origin for human chemical nociception. Nature 464, 597–600 (2010).

    Article  CAS  Google Scholar 

  13. Bounoutas, A. & Chalfie, M. Touch sensitivity in Caenorhabditis elegans. Pflugers Arch. 454, 691–702 (2007).

    Article  CAS  Google Scholar 

  14. Garcia-Anoveros, J. & Corey, D.P. The molecules of mechanosensation. Annu. Rev. Neurosci. 20, 567–594 (1997).

    Article  CAS  Google Scholar 

  15. Price, M.P. et al. The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 32, 1071–1083 (2001).

    Article  CAS  Google Scholar 

  16. Driscoll, M. & Chalfie, M. The mec-4 gene is a member of a family of Caenorhabditis elegans genes that can mutate to induce neuronal degeneration. Nature 349, 588–593 (1991).

    Article  CAS  Google Scholar 

  17. O'Hagan, R., Chalfie, M. & Goodman, M.B. The MEC-4 DEG/ENaC channel of Caenorhabditis elegans touch receptor neurons transduces mechanical signals. Nat. Neurosci. 8, 43–50 (2005).

    Article  CAS  Google Scholar 

  18. Kaplan, J.M. & Horvitz, H.R. A dual mechanosensory and chemosensory neuron in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 90, 2227–2231 (1993).

    Article  CAS  Google Scholar 

  19. Hilliard, M.A., Bergamasco, C., Arbucci, S., Plasterk, R.H. & Bazzicalupo, P. Worms taste bitter: ASH neurons, QUI-1, GPA-3 and ODR-3 mediate quinine avoidance in Caenorhabditis elegans. EMBO J. 23, 1101–1111 (2004).

    Article  CAS  Google Scholar 

  20. Hilliard, M.A. et al. In vivo imaging of C. elegans ASH neurons: cellular response and adaptation to chemical repellents. EMBO J. 24, 63–72 (2005).

    Article  CAS  Google Scholar 

  21. Colbert, H.A., Smith, T.L. & Bargmann, C.I. OSM-9, a novel protein with structural similarity to channels, is required for olfaction, mechanosensation, and olfactory adaptation in C. elegans. J. Neurosci. 17, 8259–8269 (1997).

    Article  CAS  Google Scholar 

  22. Tobin, D. et al. Combinatorial expression of TRPV channel proteins defines their sensory functions and subcellular localization in C. elegans neurons. Neuron 35, 307–318 (2002).

    Article  CAS  Google Scholar 

  23. Kindt, K.S. et al. Caenorhabditis elegans TRPA-1 functions in mechanosensation. Nat. Neurosci. 10, 568–577 (2007).

    Article  CAS  Google Scholar 

  24. Yassin, L., Samson, A.O., Halevi, S., Eshel, M. & Treinin, M. Mutations in the extracellular domain and in the membrane-spanning domains interfere with nicotinic acetylcholine receptor maturation. Biochemistry 41, 12329–12335 (2002).

    Article  CAS  Google Scholar 

  25. Huang, M. & Chalfie, M. Gene interactions affecting mechanosensory transduction in Caenorhabditis elegans. Nature 367, 467–470 (1994).

    Article  CAS  Google Scholar 

  26. Chelur, D.S. et al. The mechanosensory protein MEC-6 is a subunit of the C. elegans touch-cell degenerin channel. Nature 420, 669–673 (2002).

    Article  CAS  Google Scholar 

  27. Way, J.C. & Chalfie, M. The mec-3 gene of Caenorhabditis elegans requires its own product for maintained expression and is expressed in three neuronal cell types. Genes Dev. 3, 1823–1833 (1989).

    Article  CAS  Google Scholar 

  28. Croll, N.A. Components and patterns in the behaviour of the nematode, Caenorhabditis elegans. J. Zool. 176, 159–176 (1975).

    Article  Google Scholar 

  29. Gray, J.M., Hill, J.J. & Bargmann, C.I. A circuit for navigation in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 102, 3184–3191 (2005).

    Article  CAS  Google Scholar 

  30. Srivastava, N., Clark, D.A. & Samuel, A.D. Temporal analysis of stochastic turning behavior of swimming C. elegans. J. Neurophysiol. 102, 1172–1179 (2009).

    Article  Google Scholar 

  31. Driscoll, M. & Chalfie, M. The mec-4 gene is a member of a family of Caenorhabditis elegans genes that can mutate to induce neuronal degeneration. Nature 349, 588–593 (1991).

    Article  CAS  Google Scholar 

  32. Goodman, M.B. et al. MEC-2 regulates C. elegans DEG/ENaC channels needed for mechanosensation. Nature 415, 1039–1042 (2002).

    Article  CAS  Google Scholar 

  33. Bianchi, L. et al. The neurotoxic MEC-4(d) DEG/ENaC sodium channel conducts calcium: implications for necrosis initiation. Nat. Neurosci. 7, 1337–1344 (2004).

    Article  CAS  Google Scholar 

  34. Goodman, M.B. Mechanosensation. in WormBook (ed. The C. elegans Research Community) doi:10.1895/wormbook.1.62.1 <http://www.wormbook.org/> (2006).

  35. Smith, C.J. et al. Time-lapse imaging and cell-specific expression profiling reveal dynamic branching and molecular determinants of a multi-dendritic nociceptor in C. elegans. Dev. Biol. (in the press).

  36. Esposito, G., Di Schiavi, E., Bergamasco, C. & Bazzicalupo, P. Efficient and cell specific knock-down of gene function in targeted C. elegans neurons. Gene 395, 170–176 (2007).

    Article  CAS  Google Scholar 

  37. Tsalik, E.L. et al. LIM homeobox gene-dependent expression of biogenic amine receptors in restricted regions of the C. elegans nervous system. Dev. Biol. 263, 81–102 (2003).

    Article  CAS  Google Scholar 

  38. Wu, J., Duggan, A. & Chalfie, M. Inhibition of touch cell fate by egl-44 and egl-46 in C. elegans. Genes Dev. 15, 789–802 (2001).

    Article  CAS  Google Scholar 

  39. Zhang, S. et al. MEC-2 is recruited to the putative mechanosensory complex in C. elegans touch receptor neurons through its stomatin-like domain. Curr. Biol. 14, 1888–1896 (2004).

    Article  CAS  Google Scholar 

  40. Suzuki, H. et al. In vivo imaging of C. elegans mechanosensory neurons demonstrates a specific role for the MEC-4 channel in the process of gentle touch sensation. Neuron 39, 1005–1017 (2003).

    Article  CAS  Google Scholar 

  41. Hall, D. & Altun, Z.F. C. elegans Atlas (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2008).

  42. Zhong, L., Hwang, R.Y. & Tracey, W.D. Pickpocket is a DEG/ENaC protein required for mechanical nociception in Drosophila larvae. Curr. Biol. 20, 429–434 (2010).

    Article  CAS  Google Scholar 

  43. Kamath, R.S., Martinez-Campos, M., Zipperlen, P., Fraser, A.G. & Ahringer, J. Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol. 2, 2 (2001).

    Google Scholar 

  44. Sönnichsen, B. et al. Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans. Nature 434, 462–469 (2005).

    Article  Google Scholar 

  45. Von Stetina, S.E. et al. UNC-4 represses CEH-12/HB9 to specify synaptic inputs to VA motor neurons in C. elegans. Genes Dev. 21, 332–346 (2007).

    Article  CAS  Google Scholar 

  46. Von Stetina, S.E. et al. Cell-specific microarray profiling experiments reveal a comprehensive picture of gene expression in the C. elegans nervous system. Genome Biol. 8, R135 (2007).

    Article  Google Scholar 

  47. Fox, R.M. et al. A gene expression fingerprint of C. elegans embryonic motor neurons. BMC Genomics 6, 42 (2005).

    Article  Google Scholar 

  48. Watson, J.D. et al. Complementary RNA amplification methods enhance microarray identification of transcripts expressed in the C. elegans nervous system. BMC Genomics 9, 84 (2008).

    Article  Google Scholar 

  49. Kerr, R. et al. Optical imaging of calcium transients in neurons and pharyngeal muscle of C. elegans. Neuron 26, 583–594 (2000).

    Article  CAS  Google Scholar 

  50. Kerr, R.A. Imaging the activity of neurons and muscles. in WormBook (ed. The C. elegans Research Community) doi:10.1895/wormbook.1.113.1 <http://www.wormbook.org/> (2006).

    Google Scholar 

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Acknowledgements

We thank the Caenorhabditis Genetics Center, the National Bioresource Project and the Mitani laboratory for worm strains, N. Barry for help with microscopy, I. Rabinowitz for writing software to analyze averaged ratio traces, D. Cattermole and P. Heard in the LMB technical workshop for designing and building thermal controllers, the Vanderbilt Functional Genomics Shared Resource for help with microarray experiments and R. Branicky for comments on the manuscript. This research was supported by the Medical Research Council and grants from the National Institute on Drug Abuse (W.R.S.) and the National Institute of Neurological Disorders and Stroke (M.D. and D.M.M.), from the Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Education, Science and Technology of Korea (code M103KV010015-06K2201-01510) and National Research Foundation of Korea (codes KRF-2008-331-E00457 and 2009-0076543) to S.W.H., and from the US-Israel Binational Science Foundation (grant 2005036 to M.T. and D.M.M.).

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Authors and Affiliations

  1. Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, UK

    Marios Chatzigeorgiou & William R Schafer

  2. Korea University Graduate School of Medicine, Seoul, Korea.,

    Sungjae Yoo & Sun Wook Hwang

  3. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA.,

    Joseph D Watson, W Clay Spencer & David M Miller III

  4. Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA.,

    Wei-Hsiang Lee & Monica Driscoll

  5. Division of Biology, University of California, San Diego, La Jolla, California, USA.,

    Katie S Kindt & William R Schafer

  6. Department of Medical Neurobiology, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.,

    Millet Treinin

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Contributions

Unless otherwise noted, experiments were conducted and analyzed by M.C. under the guidance of W.R.S. Mammalian TRPA-1 expression and electrophysiology experiments were conducted by S.Y. under the guidance of S.W.H. J.D.W. generated the microarry data for PVD expression profiling using an mRNA tagging strain constructed by W.C.S. D.M.M. and M.T. supervised this work and helped with analysis. M.T. first observed the nociceptor-like morphology of PVD. K.S.K. generated the cameleon line for PVD and FLP imaging. W.-H.L. initially characterized the harsh touch behavior of mec-10 and generated the mec-10 mec-4 double mutants under the guidance of M.D. W.R.S. wrote the paper with feedback from the other authors.

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Correspondence to William R Schafer.

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Chatzigeorgiou, M., Yoo, S., Watson, J. et al. Specific roles for DEG/ENaC and TRP channels in touch and thermosensation in C. elegans nociceptors. Nat Neurosci 13, 861–868 (2010). https://doi.org/10.1038/nn.2581

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