Insect GPCRs and TRP Channels: Putative Targets for Insect Repellents

  • Kim, Sang Hoon (Department of Biological Chemistry, Johns Hopkins University School of Medicine)
  • Received : 2013.07.18
  • Accepted : 2013.07.31
  • Published : 2013.09.30


Many insects such as mosquitoes cause life-threatening diseases such as malaria, yellow fever and West Nile virus. Malaria alone infects 500 million people annually and causes 1-3 million death per year. Volatile insect repellents, which are detected through the sense of smell, have long been used to protect humans against insect pests. Antifeed-ants are non-volatile aversive compounds that are detected through the sense of taste and prevent insects from feeding on plants. The molecular targets and signaling path-ways required for sensing insect repellents and antifeedants are poorly understood. Transient Receptor Potential (TRP) Ca2+-permeable cation channels exist in organisms ranging from C. elegans to D. melanogaster and Homo sapiens. Drosophila has 13 family members, which mainly function in sensory physiology such as vision, thermotaxis and chemotaxis. G protein-coupled receptors (GPCRs) initiate olfactory signaling cascades in mammals and in nematodes C.elegans. However, the mechanisms of G protein signaling cascades in insect chemosensation are controversial. In this review, I will discuss the putative roles of G protein-coupled receptors (GPCRs) and Transient Receptor Potential (TRP) channels as targets for insect repellents.


  1. Snow, R. W., Guerra, C. A., Noor, A. M., Myint, H. Y., and Hay, S. I. (2005). The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434, 214-217.
  2. Pimentel, D. (2009) Pesticides and Pest Control. In: R. Peshin and A. Dhawan, editors. Integrated Pest Management: Innovation-Development Process: Springer Netherlands. pp. 83-87.
  3. van der Goes van Naters, W., and Carlson, J. R. (2006). Insects as chemosensors of humans and crops. Nature 444, 302-307.
  4. Katz, T. M., Miller, J. H., and Hebert, A. A. (2008). Insect repellents: historical perspectives and new developments. Journal of the American Academy of Dermatology 58, 865-871.
  5. Isman, M. B. (2006). Botanical insecticides, deterrents, and repellents in modern agriculture and an increasingly regulated world. Annual Review of Entomology 51, 45-66.
  6. Omolo, M. O., Okinyo, D., Ndiege, I. O., Lwande, W., and Hassanali, A. (2004). Repellency of essential oils of some Kenyan plants against Anopheles gambiae. Phytochemistry 65, 2797-2802.
  7. Vosshall, L. B., and Stocker, R. F. (2007). Molecular architecture of smell and taste in Drosophila. Annual Review of Neuroscience 30, 505-533.
  8. Laissue, P. P., and Vosshall, L. B. (2008). The olfactory sensory map in Drosophila. Advances in Experimental Medicine and Biology 628, 102-114.
  9. Stocker, R. F. (2001). Drosophila as a focus in olfactory research: mapping of olfactory sensilla by fine structure, odor specificity, odorant receptor expression, and central connectivity. Microscopy Research and Technique 55, 284-296.
  10. Clyne, P. J., Warr, C. G., Freeman, M. R., Lessing, D., Kim, J., and Carlson, J. R. (1999). A novel family of divergent seven-transmembrane proteins: candidate odorant receptors in Drosophila. Neuron 22, 327-338.
  11. Vosshall, L. B., Amrein, H., Morozov, P. S., Rzhetsky, A., and Axel, R. (1999). A spatial map of olfactory receptor expression in the Drosophila antenna. Cell 96, 725-736.
  12. Larsson, M. C., Domingos, A. I., Jones, W. D., Chiappe, M. E., Amrein, H., and Vosshall, L. B. (2004). Or83b encodes a broadly expressed odorant receptor essential for Drosophila olfaction. Neuron 43, 703-714.
  13. Goldman, A. L., Van der Goes van Naters, W., Lessing, D., Warr, C. G., and Carlson, J. R. (2005). Coexpression of two functional odor receptors in one neuron. Neuron 45, 661-666.
  14. Hallem, E. A., Dahanukar, A., and Carlson, J. R. (2006). Insect odor and taste receptors. Annual Review of Entomology 51, 113-135.
  15. Kreher, S. A., Kwon, J. Y., and Carlson, J. R. (2005). The molecular basis of odor coding in the Drosophila larva. Neuron 46, 445-456.
  16. Clyne, P., Grant, A., O'Connell, R., and Carlson, J. R. (1997). Odorant response of individual sensilla on the Drosophila antenna. Invertebrate Neuroscience: IN 3, 127-135.
  17. Ha, T. S., and Smith, D. P. (2006). A pheromone receptor mediates 11-cisvaccenyl acetate-induced responses in Drosophila. The Journal of neuroscience : the Official Journal of the Society for Neuroscience 26, 8727-8733.
  18. Yao, C. A., Ignell, R., and Carlson, J. R. (2005). Chemosensory coding by neurons in the coeloconic sensilla of the Drosophila antenna. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 25, 8359-8367.
  19. Benton, R., Vannice, K. S., Gomez-Diaz, C., and Vosshall, L. B. (2009). Variant ionotropic glutamate receptors as chemosensory receptors in Drosophila. Cell 136, 149-162.
  20. Montell, C. (2009). A taste of the Drosophila gustatory receptors. Current Opinion in Neurobiology 19, 345-353.
  21. Thorne, N., Chromey, C., Bray, S., and Amrein, H. (2004). Taste perception and coding in Drosophila. Current Biology : CB 14, 1065-1079.
  22. Hiroi, M., Marion-Poll, F., and Tanimura, T. (2002). Differentiated response to sugars among labellar chemosensilla in Drosophila. Zoological Science 19, 1009-1018.
  23. Hiroi, M., Meunier, N., Marion-Poll, F., and Tanimura, T. (2004). Two antagonistic gustatory receptor neurons responding to sweet-salty and bitter taste in Drosophila. Journal of Neurobiology 61, 333-342.
  24. Stocker, R. F. (1994). The organization of the chemosensory system in Drosophila melanogaster: a review. Cell and Tissue Research 275, 3-26.
  25. Clyne, P. J., Warr, C. G., and Carlson, J. R. (2000). Candidate taste receptors in Drosophila. Science 287, 1830-1834.
  26. Robertson, H. M., Warr, C. G., and Carlson, J. R. (2003). Molecular evolution of the insect chemoreceptor gene superfamily in Drosophila melanogaster. Proceedings of the National Academy of Sciences of the United States of America 100 Suppl 2, 14537-14542.
  27. Chyb, S., Dahanukar, A., Wickens, A., and Carlson, J. R. (2003). Drosophila Gr5a encodes a taste receptor tuned to trehalose. Proceedings of the National Academy of Sciences of the United States of America 100 Suppl 2, 14526-14530.
  28. Ueno, K., Ohta, M., Morita, H., Mikuni, Y., Nakajima, S., Yamamoto, K., and Isono, K. (2001). Trehalose sensitivity in Drosophila correlates with mutations in and expression of the gustatory receptor gene Gr5a. Current Biology : CB 11, 1451-1455.
  29. Wang, Z., Singhvi, A., Kong, P., and Scott, K. (2004). Taste representations in the Drosophila brain. Cell 117, 981-991.
  30. Venkatachalam, K., and Montell, C. (2007). TRP channels. Annual Review of Biochemistry 76, 387-417.
  31. Montell, C., Jones, K., Hafen, E., and Rubin, G. (1985). Rescue of the Drosophila phototransduction mutation trp by germline transformation. Science 230, 1040-1043.
  32. Montell, C., and Rubin, G. M. (1989). Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction. Neuron 2, 1313-1323.
  33. Lee, Y., Lee, Y., Lee, J., Bang, S., Hyun, S., Kang, J., Hong, S. T., Bae, E., Kaang, B. K., and Kim, J. (2005). Pyrexia is a new thermal transient receptor potential channel endowing tolerance to high temperatures in Drosophila melanogaster. Nature Genetics 37, 305-310.
  34. Neely, G. G., Keene, A. C., Duchek, P., Chang, E. C., Wang, Q. P., Aksoy, Y. A., Rosenzweig, M., Costigan, M., Woolf, C. J., Garrity, P. A., et al. (2011). TrpA1 regulates thermal nociception in Drosophila. PloS One 6, e24343.
  35. Tracey, W. D., Jr., Wilson, R. I., Laurent, G., and Benzer, S. (2003). painless, a Drosophila gene essential for nociception. Cell 113, 261-273.
  36. Gong, Z., Son, W., Chung, Y. D., Kim, J., Shin, D. W., McClung, C. A., Lee, Y., Lee, H. W., Chang, D. J., Kaang, B. K., et al. (2004). Two interdependent TRPV channel subunits, inactive and Nanchung, mediate hearing in Drosophila. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 24, 9059-9066.
  37. Kim, J., Chung, Y. D., Park, D. Y., Choi, S., Shin, D. W., Soh, H., Lee, H. W., Son, W., Yim, J., Park, C. S., et al. (2003). A TRPV family ion channel required for hearing in Drosophila. Nature 424, 81-84.
  38. Sun, Y., Liu, L., Ben-Shahar, Y., Jacobs, J. S., Eberl, D. F., and Welsh, M. J. (2009). TRPA channels distinguish gravity sensing from hearing in Johnston's organ. Proceedings of the National Academy of Sciences of the United States of America 106, 13606-13611.
  39. Kahn-Kirby, A. H., and Bargmann, C. I. (2006). TRP channels in C. elegans. Annual Review of Physiology 68, 719-736.
  40. Feng, Z., Li, W., Ward, A., Piggott, B. J., Larkspur, E. R., Sternberg, P. W., and Xu, X. Z. (2006). A C. elegans model of nicotine-dependent behavior: regulation by TRP-family channels. Cell 127, 621-633.
  41. Bandell, M., Story, G. M., Hwang, S. W., Viswanath, V., Eid, S. R., Petrus, M. J., Earley, T. J., and Patapoutian, A. (2004). Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41, 849-857.
  42. Kwon, Y., Kim, S. H., Ronderos, D. S., Lee, Y., Akitake, B., Woodward, O. M., Guggino, W. B., Smith, D. P., and Montell, C. (2010). Drosophila TRPA1 channel is required to avoid the naturally occurring insect repellent citronellal. Current Biology : CB 20, 1672-1678.
  43. Kim, S. H., Lee, Y., Akitake, B., Woodward, O. M., Guggino, W. B., and Montell, C. (2010). Drosophila TRPA1 channel mediates chemical avoidance in gustatory receptor neurons. Proceedings of the National Academy of Sciences of the United States of America 107, 8440-8445.
  44. Kang, K., Pulver, S. R., Panzano, V. C., Chang, E. C., Griffith, L. C., Theobald, D. L., and Garrity, P. A. (2010). Analysis of Drosophila TRPA1 reveals an ancient origin for human chemical nociception. Nature 464, 597-600.
  45. Al-Anzi, B., Tracey, W. D., Jr., and Benzer, S. (2006). Response of Drosophila to wasabi is mediated by painless, the fly homolog of mammalian TRPA1/ANKTM1. Current Biology : CB 16, 1034-1040.
  46. Meeusen, T., Mertens, I., De Loof, A., and Schoofs, L. (2003). G proteincoupled receptors in invertebrates: a state of the art. International Review of Cytology 230, 189-261.
  47. Wettschureck, N., and Offermanns, S. (2005). Mammalian G proteins and their cell type specific functions. Physiological Reviews 85, 1159-1204.
  48. Pifferi, S., Boccaccio, A., and Menini, A. (2006). Cyclic nucleotide-gated ion channels in sensory transduction. FEBS Letters 580, 2853-2859.
  49. Benton, R., Sachse, S., Michnick, S. W., and Vosshall, L. B. (2006). Atypical membrane topology and heteromeric function of Drosophila odorant receptors in vivo. PLoS Biology 4, e20.
  50. Lundin, C., Kall, L., Kreher, S. A., Kapp, K., Sonnhammer, E. L., Carlson, J. R., Heijne, G., and Nilsson, I. (2007). Membrane topology of the Drosophila OR83b odorant receptor. FEBS Letters 581, 5601-5604.
  51. Smart, R., Kiely, A., Beale, M., Vargas, E., Carraher, C., Kralicek, A. V., Christie, D. L., Chen, C., Newcomb, R. D., and Warr, C. G. (2008). Drosophila odorant receptors are novel seven transmembrane domain proteins that can signal independently of heterotrimeric G proteins. Insect Biochemistry and Molecular Biology 38, 770-780.
  52. Wistrand, M., Kall, L., and Sonnhammer, E. L. (2006). A general model of G protein-coupled receptor sequences and its application to detect remote homologs. Protein Science : a Publication of the Protein Society 15, 509-521.
  53. Sato, K., Pellegrino, M., Nakagawa, T., Nakagawa, T., Vosshall, L. B., and Touhara, K. (2008). Insect olfactory receptors are heteromeric ligandgated ion channels. Nature 452, 1002-1006.
  54. Wicher, D., Schafer, R., Bauernfeind, R., Stensmyr, M. C., Heller, R., Heinemann, S. H., and Hansson, B. S. (2008). Drosophila odorant receptors are both ligand-gated and cyclic-nucleotide-activated cation channels. Nature 452, 1007-1011.
  55. Nakagawa, T., and Vosshall, L. B. (2009). Controversy and consensus: noncanonical signaling mechanisms in the insect olfactory system. Current Opinion in Neurobiology 19, 284-292.
  56. Boto, T., Gomez-Diaz, C., and Alcorta, E. (2010). Expression analysis of the 3 G-protein subunits, Galpha, Gbeta, and Ggamma, in the olfactory receptor organs of adult Drosophila melanogaster. Chemical Senses 35, 183-193.
  57. Jacquin-Joly, E., Francois, M. C., Burnet, M., Lucas, P., Bourrat, F., and Maida, R. (2002). Expression pattern in the antennae of a newly isolated lepidopteran Gq protein alpha subunit cDNA. European Journal of Biochemistry / FEBS 269, 2133-2142.
  58. Kain, P., Chakraborty, T. S., Sundaram, S., Siddiqi, O., Rodrigues, V., and Hasan, G. (2008). Reduced odor responses from antennal neurons of G(q)alpha, phospholipase Cbeta, and rdgA mutants in Drosophila support a role for a phospholipid intermediate in insect olfactory transduction. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 28, 4745-4755.
  59. Laue, M., Maida, R., and Redkozubov, A. (1997). G-protein activation, identification and immunolocalization in pheromone-sensitive sensilla trichodea of moths. Cell and Tissue Research 288, 149-158.
  60. Miura, N., Atsumi, S., Tabunoki, H., and Sato, R. (2005). Expression and localization of three G protein alpha subunits, Go, Gq, and Gs, in adult antennae of the silkmoth (Bombyx mori). The Journal of Comparative Neurology 485, 143-152.
  61. Talluri, S., Bhatt, A., and Smith, D. P. (1995). Identification of a Drosophila G protein alpha subunit (dGq alpha-3) expressed in chemosensory cells and central neurons. Proceedings of the National Academy of Sciences of the United States of America 92, 11475-11479.
  62. Perez, C. A., Huang, L., Rong, M., Kozak, J. A., Preuss, A. K., Zhang, H., Max, M., and Margolskee, R. F. (2002). A transient receptor potential channel expressed in taste receptor cells. Nature Neuroscience 5, 1169-1176.
  63. Zhang, Y., Hoon, M. A., Chandrashekar, J., Mueller, K. L., Cook, B., Wu, D., Zuker, C. S., and Ryba, N. J. (2003). Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. Cell 112, 293-301.
  64. Bachmanov, A. A., and Beauchamp, G. K. (2007). Taste receptor genes. Annual Review of Nutrition 27, 389-414.
  65. Nelson, G., Chandrashekar, J., Hoon, M. A., Feng, L., Zhao, G., Ryba, N. J., and Zuker, C. S. (2002). An amino-acid taste receptor. Nature 416, 199-202.
  66. Nelson, G., Hoon, M. A., Chandrashekar, J., Zhang, Y., Ryba, N. J., and Zuker, C. S. (2001). Mammalian sweet taste receptors. Cell 106, 381-390.
  67. Meyerhof, W., Batram, C., Kuhn, C., Brockhoff, A., Chudoba, E., Bufe, B., Appendino, G., and Behrens, M. (2010). The molecular receptive ranges of human TAS2R bitter taste receptors. Chemical Senses 35, 157-170.
  68. Glendinning, J. I., Davis, A., and Ramaswamy, S. (2002). Contribution of different taste cells and signaling pathways to the discrimination of "bitter" taste stimuli by an insect. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 22, 7281-7287.
  69. Glendinning, J. I., and Hills, T. T. (1997). Electrophysiological evidence for two transduction pathways within a bitter-sensitive taste receptor. Journal of neurophysiology 78, 734-745.
  70. Sato, K., Tanaka, K., and Touhara, K. (2011). Sugar-regulated cation channel formed by an insect gustatory receptor. Proceedings of the National Academy of Sciences of the United States of America 108, 11680-11685.
  71. Ueno, K., Kohatsu, S., Clay, C., Forte, M., Isono, K., and Kidokoro, Y. (2006). Gsalpha is involved in sugar perception in Drosophila melanogaster. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 26, 6143-6152.
  72. Bredendiek, N., Hutte, J., Steingraber, A., Hatt, H., Gisselmann, G., and Neuhaus, E. M. (2011). Go alpha is involved in sugar perception in Drosophila. Chemical Senses 36, 69-81.
  73. Ditzen, M., Pellegrino, M., and Vosshall, L. B. (2008). Insect odorant receptors are molecular targets of the insect repellent DEET. Science 319, 1838-1842.
  74. Dogan, E. B., Ayres, J. W., and Rossignol, P. A. (1999). Behavioural mode of action of deet: inhibition of lactic acid attraction. Medical and Veterinary Entomology 13, 97-100.
  75. Syed, Z., and Leal, W. S. (2008). Mosquitoes smell and avoid the insect repellent DEET. Proceedings of the National Academy of Sciences of the United States of America 105, 13598-13603.
  76. Kain, P., Badsha, F., Hussain, S. M., Nair, A., Hasan, G., and Rodrigues, V. (2010). Mutants in phospholipid signaling attenuate the behavioral response of adult Drosophila to trehalose. Chemical Senses 35, 663-673.