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  • Review Article
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TRP channels in mechanosensation: direct or indirect activation?

Key Points

  • Although many ion channels are implicated in mechanosensation, it is hard to be sure that such channels are directly gated by mechanical force. Criteria that help to establish direct gating include specific tests such as: does mechanosensation involve direct activation of a channel? does the candidate protein participate in mechanical transduction? is the candidate protein mechanically sensitive? is the candidate protein a pore-forming subunit? and is the candidate protein a force-sensing subunit?

  • Various transient receptor potential (TRP) channels are involved in mechanosensation in non-neural cells — including TRPC1 in oocytes, TRPC3 and TRPC6 in myogenic tone, TRPV1 in bladder, PKD1 and PKD2 in flow-sensing in kidney and TRPV4 in osmosensing. It is difficult to establish direct gating for most of these, partly because the stimuli are slow; evidence suggests that many of them are activated by second messengers.

  • Forward genetics has revealed a role for TRP channels in Caenorhabditis elegans mechanosensation, specifically, for the worm homologues of PKD1 and PKD2 in male sensation of vulva location and for OSM-9 and OCR-2 in nose touch and osmosensation. Remarkably, the vertebrate TRPV4 can rescue mutations in the worm OSM-9, when expressed in worm sensory neurons.

  • The ability of Drosophila melanogaster to respond to painful heat and touch stimuli involves painless, a TRP channel expressed in multidendritic neurons, and TRPN1, a bristle deflection sensor. Bristle deflection almost certainly involves a directly gated channel, which may be TRPN1 itself.

  • Three TRP channels (TRPN1, Nanchung and Inactive) are required for proper hearing in Drosophila, a process that involves mechanosensation of the sound-evoked rotation of the antenna, but it is not clear which is the direct sensor and which have the necessary supporting roles.

  • A variety of TRP channels that sense sound and head movements are expressed by hair cells of the vertebrate inner ear; these include TRPV4, TRPML3 and TRPA1. There is some evidence that supports a role for each of them in mechanosensation, but there is more evidence that casts doubt on a direct involvement. At present there is no good candidate for the hair-cell transduction channel.

  • The short latency of the receptor current in vertebrate touch and proprioceptive neurons suggests direct gating of a still unidentified mechanosensory channel. One TRP channel, TRPA1, is involved in sensing painful mechanical stimuli but it may be activated downstream of the true force sensor or simply control the environment of the true transduction channel.

Abstract

Ion channels of the transient receptor potential (TRP) superfamily are involved in a wide variety of neural signalling processes, most prominently in sensory receptor cells. They are essential for mechanosensation in systems ranging from fruitfly hearing, to nematode touch, to mouse mechanical pain. However, it is unclear in many instances whether a TRP channel directly transduces the mechanical stimulus or is part of a downstream signalling pathway. Here, we propose criteria for establishing direct mechanical activation of ion channels and review these criteria in a number of mechanosensory systems in which TRP channels are involved.

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Figure 1: Phylogeny of representative TRP channels.
Figure 2: Domain structures of some TRP channels.
Figure 3: Touch sensation in nematodes.
Figure 4: Mechanosensory organs in the fruitfly.
Figure 5: Mechanotransduction in vertebrate hair cells.

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References

  1. Montell, C. The TRP superfamily of cation channels. Sci. STKE [online] 272, re3 (2005).

    Google Scholar 

  2. Schaefer, M. Homo- and heteromeric assembly of TRP channel subunits. Pflugers Arch. 451, 35–42 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Owsianik, G., Talaver, K., Voets, T. & Nilius, B. Permeation and selectivity of TRP channels. Annu. Rev. Physiol. 68, 685–717 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Clapham, D. E. TRP channels as cellular sensors. Nature 426, 517–524 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Voets, T., Talavera, K., Owsianik, G. & Nilius, B. Sensing with TRP channels. Nature Chem. Biol. 1, 85–92 (2005).

    Article  CAS  Google Scholar 

  6. Lin, S. Y. & Corey, D. P. TRP channels in mechanosensation. Curr. Opin. Neurobiol. 15, 350–357 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Methfessel, C., Witzemann, V., Takahashi, T., Mishina, M., Numa, S. & Sakmann, B. Patch clamp measurements on Xenopus laevis oocytes: currents through endogenous channels and implanted acetylcholine receptor and sodium channels. Pflugers Arch. 407, 577–588 (1986).

    Article  CAS  PubMed  Google Scholar 

  8. Hamill, O. P. & McBride, D. W. Jr. Rapid adaptation of single mechanosensitive channels in Xenopus oocytes. Proc. Natl Acad. of Sci. USA 89, 7462–7466 (1992).

    Article  CAS  Google Scholar 

  9. Maroto, R. et al. TRPC1 forms the stretch-activated cation channel in vertebrate cells. Nature Cell Biol. 7, 179–185 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Davis, M. J. & Hill, M. A. Signaling mechanisms underlying the vascular myogenic response. Physiol. Rev. 79, 387–423 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Welsh, D. G., Morielli, A. D., Nelson, M. T. & Brayden, J. E. Transient receptor potential channels regulate myogenic tone of resistance arteries. Circ. Res. 90, 248–250 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Dietrich, A. et al. Increased vascular smooth muscle contractility in TRPC6−/− mice. Mol. Cell Biol. 25, 6980–6989 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Earley, S., Waldron, B. J. & Brayden, J. E. Critical role for transient receptor potential channel TRPM4 in myogenic constriction of cerebral arteries. Circ. Res. 95, 922–929 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Muraki, K. et al. TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes. Circ. Res. 93, 829–838 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Osol, G., Laher, I. & Kelley, M. Myogenic tone is coupled to phospholipase C and G protein activation in small cerebral arteries. Am. J. Physiol. 265, H415–H420 (1993).

    CAS  PubMed  Google Scholar 

  16. Spassova, M. A., Hewavitharana, T., Xu, W., Soboloff, J. & Gill, D. L. A common mechanism underlies stretch activation and receptor activation of TRPC6 channels. Proc. Natl Acad. Sci. USA 103, 16586–16591 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Oancea, E., Wolfe, J. T. & Clapham, D. E. Functional TRPM7 channels accumulate at the plasma membrane in response to fluid flow. Circ. Res. 98, 245–253 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Numata, T., Shimizu, T. & Okada, Y. TRPM7 is a stretch- and swelling-activated cation channel involved in volume regulation in human epithelial cells. Am. J. Physiol. Cell Physiol. 292, C460–C467 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Numata, T., Shimizu, T. & Okada, Y. Direct mechano-stress sensitivity of TRPM7 channel. Cell Physiol. Biochem. 19, 1–8 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Grimm, C., Kraft, R., Sauerbruch, S., Schultz, G. & Harteneck, C. Molecular and functional characterization of the melastatin-related cation channel TRPM3. J. Biol. Chem. 278, 21493–21501 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Birder, L. A. et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nature Neurosci. 5, 856–860 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Birder, L. A. et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc. Natl Acad. Sci. USA 98, 13396–13401 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Praetorius, H. A. & Spring, K. R. A physiological view of the primary cilium. Annu. Rev. Physiol. 67, 515–529 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Praetorius, H. A. & Spring, K. R. Bending the MDCK cell primary cilium increases intracellular calcium. J. Membr. Biol. 184, 71–79 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Nauli, S. M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nature Genet. 33, 129–137 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Palmer, C. P. et al. A TRP homolog in Saccharomyces cerevisiae forms an intracellular Ca2+-permeable channel in the yeast vacuolar membrane. Proc. Natl Acad. Sci. USA 98, 7801–7805 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Denis, V. & Cyert, M. S. Internal Ca2+ release in yeast is triggered by hypertonic shock and mediated by a TRP channel homologue. J. Cell Biol. 156, 29–34 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhou, X. L., Batiza, A. F., Loukin, S. H., Palmer, C. P., Kung, C. & Saimi, Y. The transient receptor potential channel on the yeast vacuole is mechanosensitive. Proc. Natl Acad. Sci. USA 100, 7105–7110 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhou, X. L., Loukin, S. H., Coria, R., Kung, C. & Saimi, Y. Heterologously expressed fungal transient receptor potential channels retain mechanosensitivity in vitro and osmotic response in vivo. Eur. Biophys. J. 34, 413–422 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Liedtke, W. et al. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103, 525–535 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Strotmann, R., Harteneck, C., Nunnenmacher, K., Schultz, G. & Plant, T. D. OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nature Cell Biol. 2, 695–702 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Wissenbach, U., Bodding, M., Freichel, M. & Flockerzi, V. Trp12, a novel Trp related protein from kidney. FEBS Lett. 485, 127–134 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Delany, N. S. et al. Identification and characterization of a novel human vanilloid receptor-like protein, VRL-2. Physiol. Genomics 4, 165–174 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Arniges, M., Vasquez, E., Fernandez-Fernandez, J. M. & Valverde, M. A. Swelling-activated Ca2+ entry via TRPV4 channel is defective in cystic fibrosis airway epithelia. J. Biol. Chem. 279, 54062–54068 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. McKinley, M. J. & Johnson, A. K. The physiological regulation of thirst and fluid intake. News Physiol. Sci. 19, 1–6 (2004).

    PubMed  Google Scholar 

  36. McKinley, M. J. et al. Physiological and pathophysiological influences on thirst. Physiol. Behav. 81, 795–803 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Bourque, C. W. & Oliet, S. H. Osmoreceptors in the central nervous system. Annu. Rev. Physiol. 59, 601–619 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Liedtke, W. & Friedman, J. M. Abnormal osmotic regulation in trpv4−/− mice. Proc. Natl Acad. Sci. USA 100, 13698–13703 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mizuno, A., Matsumoto, N., Imai, M. & Suzuki, M. Impaired osmotic sensation in mice lacking TRPV4. Am. J. Physiol. Cell Physiol. 285, C96–C101 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Xu, H., Zhao, H., Tian, W., Yoshida, K., Roullet, J. B. & Cohen, D. M. Regulation of a transient receptor potential (TRP) channel by tyrosine phosphorylation. SRC family kinase-dependent tyrosine phosphorylation of TRPV4 on TYR-253 mediates its response to hypotonic stress. J. Biol. Chem. 278, 11520–11527 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Watanabe, H. et al. Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424, 434–438 (2003). Together with reference 40, this paper shows that the activation of TRPV4 by cell swelling is indirect and dependent on a second messenger pathway.

    Article  CAS  PubMed  Google Scholar 

  42. Vriens, J. et al. Cell swelling, heat, and chemical agonists use distinct pathways for the activation of the cation channel TRPV4. Proc. Natl Acad. Sci. USA 101, 396–401 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Vriens, J. et al. Modulation of the Ca2+ permeable cation channel TRPV4 by cytochrome P450 epoxygenases in vascular endothelium. Circ. Res. 97, 908–915 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Alessandri-Haber, N., Joseph, E., Dina, O. A., Liedtke, W. & Levine, J. D. TRPV4 mediates pain-related behavior induced by mild hypertonic stimuli in the presence of inflammatory mediator. Pain 118, 70–79 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Liedtke, W., Tobin, D. M., Bargmann, C. I. & Friedman, J. M. Mammalian TRPV4 (VR-OAC) directs behavioural responses to osmotic and mechanical stimuli in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 100 (Suppl. 2), 14531–14536 (2003). TRPV4 rescues worms carrying mutated OSM-9 showing that OSM-9 is a key part of the conduction pathway for nose touch and osmosensation in C. elegans . TRPV4's pore alone rescues the mutant worms, suggesting that OSM-9 is not necessary for the gating of the channel mediating this sensation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Voets, T. et al. Molecular determinants of permeation through the cation channel TRPV4. J. Biol. Chem. 277, 33704–33710 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Sharif Naeini, R., Witty, M. F., Seguela, P. & Bourque, C. W. An N-terminal variant of Trpv1 channel is required for osmosensory transduction. Nature Neurosci. 9, 93–98 (2006).

    Article  PubMed  CAS  Google Scholar 

  48. Ciura, S. & Courque, C. W. Transient receptor potential vanilloid 1 is required for intrinsic osmoreception in organum vasculosum lamina terminalis neurons and for normal thirst responses to systemic hyperosmolality. J. Neurosci. 26, 9069–9075 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  50. O'Hagan, R., Chalfie, M. & Goodman, M. B. The MEC-4 DEG/ENaC channel of Caenorhabditis elegans touch receptor neurons transduces mechanical signals. Nature Neurosci. 8, 43–50 (2005). Transduction current in response to body touch in C. elegans is mediated by a directly mechanically gated ion channel. This channel is composed of MEC-4 and MEC-10.

    Article  CAS  PubMed  Google Scholar 

  51. 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  PubMed  PubMed Central  Google Scholar 

  52. Bargmann, C. I., Thomas, J. H. & Horvitz, H. R. Chemosensory cell function in the behavior and development of Caenorhabditis elegans. Cold Spring Harb. Symp. Quant. Biol. 55, 529–538 (1990).

    Article  CAS  PubMed  Google Scholar 

  53. 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 Caenorhabditis elegans. J. Neurosci. 17, 8259–8269 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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). Together with reference 53, this paper details the discovery of mechanosensitive TRP channels and shows how OSM-9 depends on other subunits for its proper function.

    Article  CAS  PubMed  Google Scholar 

  55. Hart, A. C., Kass, J., Shapiro, J. E. & Kaplan, J. M. Distinct signaling pathways mediate touch and osmosensory responses in a polymodal sensory neuron. J. Neurosci. 19, 1952–1958 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hart, A. C., Sims, S. & Kaplan, J. M. Synaptic code for sensory modalities revealed by C. elegans GLR-1 glutamate receptor. Nature 378, 82–85 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Maricq, A. V., Peckol, E., Driscoll, M. & Bargmann, C. I. Mechanosensory signalling in C. elegans mediated by the GLR-1 glutamate receptor. Nature 378, 78–81 (1995).

    Article  CAS  PubMed  Google Scholar 

  58. Roayaie, K., Crump, J. G., Sagasti, A. & Bargmann, C. I. The Gα protein ODR-3 mediates olfactory and nociceptive function and controls cilium morphogenesis in C. elegans olfactory neurons. Neuron 20, 55–67 (1998).

    Article  CAS  PubMed  Google Scholar 

  59. Kahn-Kirby, A. H. et al. Specific polyunsaturated fatty acids drive TRPV-dependent sensory signaling in vivo. Cell 119, 889–900 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Liu, K. S. & Sternberg, P. W. Sensory regulation of male mating behavior in Caenorhabditis elegans. Neuron 14, 79–89 (1995).

    Article  CAS  PubMed  Google Scholar 

  61. Barr, M. M. & Sternberg, P. W. A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans. Nature 401, 386–389 (1999).

    CAS  PubMed  Google Scholar 

  62. Barr, M. M. et al. The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway. Curr. Biol. 11, 1341–1346 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Tracey, W. D., Jr, Wilson, R. I., Laurent, G. & Benzer, S. painless, a Drosophila gene essential for nociception. Cell 113, 261–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Walker, R. G., Willingham, A. T. & Zuker, C. S. A Drosophila mechanosensory transduction channel. Science 287, 2229–2234 (2000). The transduction channel for bristle deflection in Drosophila is fast enough to be directly gated. Mutations in TRPN1 abolish the receptor current, implicating for the first time a TRP channel in mechanosensation.

    Article  CAS  PubMed  Google Scholar 

  65. Perkins, L. A., Hedgecock, E. M., Thomson, J. N. & Culotti, J. G. Mutant sensory cilia in the nematode Caenorhabditis elegans. Dev. Biol. 117, 456–487 (1986).

    Article  CAS  PubMed  Google Scholar 

  66. Li, W., Feng, Z., Sternberg, P. W. & Xu, X. Z. A C. elegans stretch receptor neuron revealed by a mechanosensitive TRP channel homologue. Nature 440, 684–687 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Caldwell, J. C. & Eberl, D. F. Towards a molecular understanding of Drosophila hearing. J. Neurobiol. 53, 172–189 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Eberl, D. F., Hardy, R. W. & Kernan, M. J. Genetically similar transduction mechanisms for touch and hearing in Drosophila. J. Neurosci. 20, 5981–5988 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gopfert, M. C. & Robert, D. The mechanical basis of Drosophila audition. J. Exp. Biol. 205, 1199–1208 (2002).

    Article  PubMed  Google Scholar 

  70. Gopfert, M. C. & Robert, D. Motion generation by Drosophila mechanosensory neurons. Proc. Natl Acad. Sci. USA 100, 5514–5519 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gopfert, M. C., Humphris, A. D., Albert, J. T., Robert, D. & Hendrich, O. Power gain exhibited by motile mechanosensory neurons in Drosophila ears. Proc. Natl Acad. Sci. USA 102, 325–330 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Martin, P. & Hudspeth, A. J. Compressive nonlinearity in the hair bundle's active response to mechanical stimulation. Proc. Natl Acad. Sci. USA 98, 14386–14391 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chan, D. K. & Hudspeth, A. J. Ca2+ current-driven nonlinear amplification by the mammalian cochlea in vitro. Nature Neurosci. 8, 149–155 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Cheung, E. L. & Corey, D. P. Ca2+ changes the force sensitivity of the hair-cell transduction channel. Biophys. J. 90, 124–139 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Kim, J. et al. A TRPV family ion channel required for hearing in Drosophila. Nature 424, 81–84 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Gong, Z. et al. Two interdependent TRPV channel subunits, inactive and Nanchung, mediate hearing in Drosophila. J. Neurosci. 24, 9059–9066 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gopfert, M. C., Albert, J. T., Nadrowski, B. & Kamikouchi, A. Specification of auditory sensitivity by Drosophila TRP channels. Nature Neurosci. 9, 999–1000 (2006). This study of mechanical correlates of transduction suggests that TRPN1 has a direct role in mediating the mechanical transduction in fly hearing and that Nanchung and Inactive have a modulatory role.

    Article  PubMed  CAS  Google Scholar 

  78. Corey, D. P. & Hudspeth, A. J. Response latency of vertebrate hair cells. Biophys. J. 26, 499–506 (1979). An early paper suggesting that fast activation implies that a channel is directly gated by mechanical force.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ricci, A. J., Kennedy, H. J., Crawford, A. C. & Fettiplace, R. The transduction channel filter in auditory hair cells. J. Neurosci. 25, 7831–7839 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Corey, D. P. & Hudspeth, A. J. Kinetics of the receptor current in bullfrog saccular hair cells. J. Neurosci. 3, 962–976 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Howard, J. & Hudspeth, A. J. Compliance of the hair bundle associated with gating of mechanoelectrical transduction channels in the bullfrog's saccular hair cell. Neuron 1, 189–199 (1988). The first paper to show a mechanical correlate of ion channel gating.

    Article  CAS  PubMed  Google Scholar 

  82. Meyers, J. R. et al. Lighting up the senses: FM1–43 loading of sensory cells through nonselective ion channels. J. Neurosci. 23, 4054–4065 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sidi, S., Friedrich, R. W. & Nicolson, T. NompC TRP channel required for vertebrate sensory hair cell mechanotransduction. Science 301, 96–99 (2003). Presents the first experimental evidence that a TRP channel is the hair-cell transduction channel. Later studies, such as reference 84, lessen the strength of this evidence.

    Article  CAS  PubMed  Google Scholar 

  84. Shin, J. B. et al. Xenopus TRPN1 (NOMPC) localizes to microtubule-based cilia in epithelial cells, including inner-ear hair cells. Proc. Natl Acad. Sci. USA 102, 12572–12577 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Di Palma, F. et al. Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice. Proc. Natl Acad. Sci. USA 99, 14994–14999 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ohmori, H. Mechano-electrical transduction currents in isolated vestibular hair cells of the chick. J. Physiol. 359, 189–217 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tabuchi, K., Suzuki, M., Mizuno, A. & Hara, A. Hearing impairment in TRPV4 knockout mice. Neurosci. Lett. 382, 304–308 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. 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  PubMed  Google Scholar 

  89. Jordt, S. E. et al. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427, 260–265 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  91. Macpherson, L. J. et al. The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr. Biol. 15, 929–934 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Bautista, D. M. et al. Pungent products from garlic activate the sensory ion channel TRPA1. Proc. Natl Acad. Sci. USA 102, 12248–12252 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Corey, D. P. et al. TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature 432, 723–730 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Nagata, K., Duggan, A., Kumar, G. & Garcia-Anoveros, J. Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing. J. Neurosci. 25, 4052–4061 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Farris, H. E., LeBlanc, C. L., Goswami, J. & Ricci, A. J. Probing the pore of the auditory hair cell mechanotransducer channel in turtle. J. Physiol. 558, 769–792 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kroese, A. B., Das, A. & Hudspeth, A. J. Blockage of the transduction channels of hair cells in the bullfrog's sacculus by aminoglycoside antibiotics. Hear. Res. 37, 203–217 (1989).

    Article  CAS  PubMed  Google Scholar 

  97. Crawford, A. C., Evans, M. G. & Fettiplace, R. The actions of calcium on the mechano-electrical transducer current of turtle hair cells. J. Physiol. (Lond) 434, 269–298 (1991).

    Article  Google Scholar 

  98. Kwan, K. Y. et al. TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron 50, 277–289 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  100. Lumpkin, E. A. & Caterina, M. J. Mechanisms of sensory transduction in the skin. Nature 445, 858–865 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Drew, L. J., Wood, J. N. & Cesare, P. Distinct mechanosensitive properties of capsaicin-sensitive and insensitive sensory neurons. J. Neurosci. 22, 228 (2002).

    Article  Google Scholar 

  102. Drew, L. J. et al. Acid-sensitive ion channels ASIC2 and ASIC3 do not contributre to mechanically activated currents in mammalian sensory neurons. J. Physiol. 556, 691–710 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hu, J. & Lewin, G. R. Mechanosensitive currents in the neurites of cultured mouse sensory neurones. J. Physiol. 577, 815–828 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Suzuki, M., Mizuno, A., Kodaira, K. & Imai, M. Impaired pressure sensation in mice lacking TRPV4. J. Biol. Chem. 278, 22664–22668 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Sukharev, S. & Corey, D. P. Mechanosensitive channels: multiplicity of families and gating paradigms. Sci STKE [online] 219, re4 (2004).

    Google Scholar 

  106. Kung, C. A possible unifying principle for mechanosensation. Nature 436, 647–654 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Sukharev, S. I., Blount, P., Martinac, B., Blattner, F. R. & Kung, C. A large-conductance mechanosensitive channel in E. coli encoded by mscL alone. Nature 368, 265–268 (1994).

    Article  CAS  PubMed  Google Scholar 

  108. Sukharev, S. L., Martinac, B. & Kung, C. Reconstitution of two distinct types of mechano-sensitive channels from the E. coli cell envelope. Biophys. J. 64, A93 (1993).

    Google Scholar 

  109. Hase, C. C., Le Dain, A. C. & Martinac, B. Purification and functional reconstitution of the recombinant large mechanosensitive ion channel (MscL) of Escerichia coli. J. Biol. Chem. 270, 18329–18334 (1995).

    Article  CAS  PubMed  Google Scholar 

  110. Chiang, C. S., Anishkin, A. & Sukharev, S. Gating of the large mechanosensitive channel in situ: estimation of the spatial scale of the transition from channel population responses. Biophys. J. 86, 2846–2861 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Cruickshank, C. C., Minchin, R. F., Le Dain, A. C. & Martinac, B. Estimation of the pore size of the large-conductance mechanosensitive ion channel of Escherichia coli. Biophys. J. 73, 1925–1931 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Blount, P., Sukharev, S. I., Schoeder, M. J., Nagle, S. K. & Kung, C. Single residue substitutions that change the gating properties of a mechanosensitive channel in Escherichia coli. Proc. Natl Acad. Sci. USA 93, 11652–11657 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hase, C. C., Le Dain, A. C. & Martinac, B. Molecular dissection of the large mechanosensitive ion channel (MscL) of E. coli: mutants with altered channel gating and pressure sensitivity. J. Membr. Biol. 157, 17–25 (1997).

    Article  CAS  PubMed  Google Scholar 

  114. Chang, G., Spencer, R. H., Lee, A. T., Barclay, A. T. & Rees, D. C. Structure of the MscL homolog from Mycobacterium tuberculosis: a gated mechanosensitive ion channel. Science 282, 2220–2226 (1998).

    Article  CAS  PubMed  Google Scholar 

  115. Sukharev, S., Betanzos, M., Chiang, C. S. & Guy, H. R. The gating mechanism of the large mechanosensitive channel mscL. Nature 409, 720–724 (2001). The authors elucidate the molecular details of the gating mechanism of the best studied mechanically gated ion channel, mscL.

    Article  CAS  PubMed  Google Scholar 

  116. Gullingsrud, J., Kosztin, D. & Schulten, K. Structural determinants of MscL gating studied by molecular dynamics simulations. Biophys. J. 80, 2074–2081 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Batiza, A. F., Kuo, M. M., Yoshimura, K. & Kung, C. Gating the bacterial mechanosensitive channel mscL in vivo. Proc. Natl Acad. Sci. USA 99, 5643–5648 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Anishkin, A., Chiang, C. S. & Sukharev, S. Gain-of-function mutations reveal expanded intermediate states and a sequential action of two gates in mscL. J. Gen. Physiol. 125, 155–170 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Firsov, D., Gautschi, I., Merillat, A. M., Rossier, B. C. & Schild, L. The heterotetrameric architecture of the epithelial sodium channel (ENaC). EMBO J. 17, 344–352 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Staruschenko, A., Medina, J. L., Patel, P., Shapiro, M. S., Booth, R. E. & Stockand, J. D. Fluorescence resonance energy transfer analysis of subunit stoichiometry of the epithelial Na+ channel. J. Biol. Chem. 279, 27729–27734 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Chalfie, M. & Sulston, J. Developmental genetics of the mechanosensory neurons of Caenorhabditis elegans. Dev. Biol. 82, 358–370 (1981).

    Article  CAS  PubMed  Google Scholar 

  122. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  124. Emtage, L., Gu, G., Hartwieg, E. & Chalfie, M. Extracellular proteins organize the mechanosensory channel complex in C. elegans touch receptor neurons. Neuron 44, 795–807 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  127. Howard, J. & Bechstedt, S. Hypothesis: a helix of ankyrin repeats of the NOMPC-TRP ion channel is the gating spring of mechanoreceptors. Curr. Biol. 14, R224–R226 (2004).

    Article  CAS  PubMed  Google Scholar 

  128. Corey, D. P. & Sotomayor, M. Hearing: tightrope act. Nature 428, 901–903 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Sotomayor, M., Corey, D. P. & Schulten, K. In search of the hair-cell gating spring: Elastic properties of ankyrin and cadherin repeats. Structure 13, 669–682 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Lee, G. et al. Nanospring behaviour of ankyrin repeats. Nature 440, 246–249 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Goodman, M. B. & Schwarz, E. M. Transducing touch in Caenorhabditis elegans. Annu. Rev. Physiol. 65, 429–452 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Fitch, D. H. & Emmons, S. W. Variable cell positions and cell contacts underlie morphological evolution of the rays in the male tails of nematodes related to Caenorhabditis elegans. Dev. Biol. 170, 564–582 (1995).

    Article  CAS  PubMed  Google Scholar 

  133. Kamikouchi, A., Shimada, T. & Ito, K. Comprehensive classification of the auditory sensory projections in the brain of the fruitfly Drosophila melanogaster. J. Comp. Neurol. 499, 317–356 (2006).

    Article  PubMed  Google Scholar 

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DATABASES

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Xenopus laevis

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Glossary

Osmoregulation

A homeostatic mechanism by which cells maintain their volume despite changes in extracellular osmolarity.

Liposome

A lipid vesicle that is artificially formed by sonicating lipids in an aqueous solution.

Heterologous expression system

A system for studying the function of a protein in which a gene construct is transfected into suitable host cells such as bacteria or cultured mammalian cells that will produce the protein in a near-native environment.

Merkel cell

A specialized cell in the skin, often associated with sensory hairs, that is involved in cutaneous mechanosensation.

Circumventricular organ

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Johnston's organ

The hearing organ in insects, formed by a collection of mechanosensory neurons in the second antennal segment that respond to sound-induced rotation of the third antennal segment.

Arista

A feathery appendage of the insect antenna that is moved by acoustic stimuli.

Chordotonal organ

A sensory organ in insects that detects mechanical and sound vibrations.

Stereocilia

Elongated microvilli emanating from the apical surfaces of hair cells, composed of a dense core of crosslinked actin filaments surrounded by the cell membrane.

Endolymph

The fluid filling the scala media of the cochlea and the lumen of the vestibular organs. Endolymph has an unusual ion composition with high potassium and low sodium concentrations.

Morpholinos

Antisense oligonucleotides that block gene expression by interfering with the translation initiation complex or with RNA splicing.

Kinocilia

A single true cilium containing microtubules that emanates from the apical surfaces of hair cells, adjacent to the tallest stereocilia.

Utricle

One of three types of vertebrate vestibular organs (along with the saccule and semicircular canals) that is sensitive to linear acceleration.

Microphonic potential

An extracellular receptor potential from inner ear organs caused by current flowing through receptor cells. Like a microphone, the cochlea produces a small voltage in response to acoustic stimuli.

Slowly adapting neuron

Sensory neuron that maintains firing for the duration of a stimulus.

Rapidly adapting neuron

Sensory neuron that fires at the start of a sensory stimulus but shows a decay, or adaptation, of firing during maintained stimuli.

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Christensen, A., Corey, D. TRP channels in mechanosensation: direct or indirect activation?. Nat Rev Neurosci 8, 510–521 (2007). https://doi.org/10.1038/nrn2149

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