Biochemistry (Moscow)

, 76:882 | Cite as

Glutamate receptor RNA editing in health and disease

  • A. Barbon
  • S. BarlatiEmail author


RNA editing is a post-transcriptional process with an important role in gene modification. This editing process involves site-selective deamination of adenosine into inosine in the pre-mRNA, leading to the alteration of translation codons and splicing sites in nuclear transcripts, thereby enabling functionally distinct proteins to arise from a single gene. One important instance is the neuron editing of the ionotropic glutamate receptors (iGluRs). GluRs play a key role in excitatory synaptic transmission and plasticity in the central nervous system (CNS); their channel properties are largely dictated by the subunit composition of the tetrameric receptors. AMPA/kainate channels are assembled from GluA1-4 AMPA or GluK1-5 kainate receptor subunits. In particular, three of the four AMPA and two of the five kainate receptor subunits are subject to RNA editing. The editing positions have been named on the basis of the amino acid substitutions, such as the Q/R site in AMPA GluA2; the Q/R site in GluK1 and GluK2; the R/G site in GluA2, GluA3, and GluA4; and the I/V and Y/C sites in GluK2. These amino acid changes lead to profound alterations of the channel properties. This paper reviews the most relevant data showing the importance of glutamate receptor RNA editing in finely tuning glutamatergic neurotransmission in the normal CNS and following alterations of the editing process in association with disease phenotypes. Overall, these data indicate that a highly regulated process of glutamate receptor editing is of key importance in the proper function of neuronal cells and in their ability to adapt and modulate synaptic function.

Key words

RNA editing glutamate receptor neurological disorders 


  1. 1.
    Chen, M., and Manley, J. L. (2009) Nat. Rev. Mol. Cell Biol., 10, 741–754.PubMedGoogle Scholar
  2. 2.
    Benne, R., van den Burg, J., Brakenhoff, J. P., Sloof, P., van Boom, J. H., and Tromp, M. C. (1986) Cell, 46, 819–826.PubMedCrossRefGoogle Scholar
  3. 3.
    Smith, H. C. (2008) RNA and DNA Editing: Molecular Mechanisms and Their Integration into Biological Systems, Wiley Interscience, Hoboken, NJ, USA.Google Scholar
  4. 4.
    Farajollahi, S., and Maas, S. (2010) Trends Genet., 26, 221–230.PubMedCrossRefGoogle Scholar
  5. 5.
    Bass, B. L. (2002) Ann. Rev. Biochem., 71, 817–846.PubMedCrossRefGoogle Scholar
  6. 6.
    Traynelis, S. F., Wollmuth, L. P., McBain, C. J., Menniti, F. S., Vance, K. M., Ogden, K. K., Hansen, K. B., Yuan, H., Myers, S. J., and Dingledine, R. (2010) Pharmacol. Rev., 62, 405–496.PubMedCrossRefGoogle Scholar
  7. 7.
    Bigge, C. F. (1999) Curr. Opin. Chem. Biol., 3, 441–447.PubMedCrossRefGoogle Scholar
  8. 8.
    Dingledine, R., Borges, K., Bowie, D., and Traynelis, S. F. (1999) Pharmacol. Rev., 51, 7–61.PubMedGoogle Scholar
  9. 9.
    Collingridge, G. L., Olsen, R., Peters, J. A., and Spedding, M. (2009) Neuropharmacology, 56, 2–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Wenthold, R. J., Petralia, R. S., Blahos, J., II, and Niedzielski, A. S. (1996) J. Neurosci., 16, 1982–1989.PubMedGoogle Scholar
  11. 11.
    Sommer, B., Keinanen, K., Verdoorn, T. A., Wisden, W., Burnashev, N., Herb, A., Kohler, M., Takagi, T., Sakmann, B., and Seeburg, P. H. (1990) Science, 249, 1580–1585.PubMedCrossRefGoogle Scholar
  12. 12.
    Lambolez, B., Ropert, N., Perrais, D., Rossier, J., and Hestrin, S. (1996) Proc. Natl. Acad. Sci. USA, 93, 1797–1802.PubMedCrossRefGoogle Scholar
  13. 13.
    Hollmann, M., and Heinemann, S. (1994) Ann. Rev. Neurosci., 17, 31–108.PubMedCrossRefGoogle Scholar
  14. 14.
    Monyer, H., Seeburg, P. H., and Wisden, W. (1991) Neuron, 6, 799–810.PubMedCrossRefGoogle Scholar
  15. 15.
    Pinheiro, P. S., and Mulle, C. (2008) Nat. Rev. Neurosci., 9, 423–436.PubMedCrossRefGoogle Scholar
  16. 16.
    Monyer, H., Sprengel, R., Schoepfer, R., Herb, A., Higuchi, M., Lomeli, H., Burnashev, N., Sakmann, B., and Seeburg, P. H. (1992) Science, 256, 1217–1221.PubMedCrossRefGoogle Scholar
  17. 17.
    Schorge, S., and Colquhoun, D. (2003) J. Neurosci., 23, 1151–1158.PubMedGoogle Scholar
  18. 18.
    Ulbrich, M. H., and Isacoff, E. Y. (2008) Proc. Natl. Acad. Sci. USA, 105, 14163–14168.PubMedCrossRefGoogle Scholar
  19. 19.
    Nishikura, K. (2010) Ann. Rev. Biochem., 79, 321–349.PubMedCrossRefGoogle Scholar
  20. 20.
    Egebjerg, J., and Heinemann, S. F. (1993) Proc. Natl. Acad. Sci. USA, 90, 755–759.PubMedCrossRefGoogle Scholar
  21. 21.
    Swanson, G. T., Feldmeyer, D., Kaneda, M., and Cull-Candy, S. G. (1996) J. Physiol., 492, 129–142.PubMedGoogle Scholar
  22. 22.
    Kamboj, S. K., Swanson, G. T., and Cull-Candy, S. G. (1995) J. Physiol., 486, 297–303.PubMedGoogle Scholar
  23. 23.
    Brusa, R., Zimmermann, F., Koh, D. S., Feldmeyer, D., Gass, P., Seeburg, P. H., and Sprengel, R. (1995) Science, 270, 1677–1680.PubMedCrossRefGoogle Scholar
  24. 24.
    Feldmeyer, D., Kask, K., Brusa, R., Kornau, H. C., Kolhekar, R., Rozov, A., Burnashev, N., Jensen, V., Hvalby, O., Sprengel, R., and Seeburg, P. H. (1999) Nat. Neurosci., 2, 57–64.PubMedCrossRefGoogle Scholar
  25. 25.
    Higuchi, M., Maas, S., Single, F. N., Hartner, J., Rozov, A., Burnashev, N., Feldmeyer, D., Sprengel, R., and Seeburg, P. H. (2000) Nature, 406, 78–81.PubMedCrossRefGoogle Scholar
  26. 26.
    Schoft, V. K., Schopoff, S., and Jantsch, M. F. (2007) Nucleic Acids Res., 35, 3723–3732.PubMedCrossRefGoogle Scholar
  27. 27.
    Kask, K., Zamanillo, D., Rozov, A., Burnashev, N., Sprengel, R., and Seeburg, P. H. (1998) Proc. Natl. Acad. Sci. USA, 95, 13777–13782.PubMedCrossRefGoogle Scholar
  28. 28.
    Whitney, N. P., Peng, H., Erdmann, N. B., Tian, C., Monaghan, D. T., and Zheng, J. C. (2008) FASEB J., 22, 2888–2900.PubMedCrossRefGoogle Scholar
  29. 29.
    Greger, I. H., Khatri, L., and Ziff, E. B. (2002) Neuron, 34, 759–772.PubMedCrossRefGoogle Scholar
  30. 30.
    Greger, I. H., Khatri, L., Kong, X., and Ziff, E. B. (2003) Neuron, 40, 763–774.PubMedCrossRefGoogle Scholar
  31. 31.
    Krampfl, K., Schlesinger, F., Zorner, A., Kappler, M., Dengler, R., and Bufler, J. (2002) Eur. J. Neurosci., 15, 51–62.PubMedCrossRefGoogle Scholar
  32. 32.
    Lomeli, H., Mosbacher, J., Melcher, T., Hoger, T., Geiger, J. R., Kuner, T., Monyer, H., Higuchi, M., Bach, A., and Seeburg, P. H. (1994) Science, 266, 1709–1713.PubMedCrossRefGoogle Scholar
  33. 33.
    Koike, M., Tsukada, S., Tsuzuki, K., Kijima, H., and Ozawa, S. (2000) J. Neurosci., 20, 2166–2174.PubMedGoogle Scholar
  34. 34.
    Grosskreutz, J., Zoerner, A., Schlesinger, F., Krampfl, K., Dengler, R., and Bufler, J. (2003) Eur. J. Neurosci., 17, 1173–1178.PubMedCrossRefGoogle Scholar
  35. 35.
    Laurencikiene, J., Kallman, A. M., Fong, N., Bentley, D. L., and Ohman, M. (2006) EMBO Rep., 7, 303–307.PubMedGoogle Scholar
  36. 36.
    Ryman, K., Fong, N., Bratt, E., Bentley, D. L., and Ohman, M. (2007) RNA, 13, 1071–1078.PubMedCrossRefGoogle Scholar
  37. 37.
    Penn, A. C., and Greger, I. H. (2009) RNA Biol., 6, 517–521.PubMedCrossRefGoogle Scholar
  38. 38.
    Barbon, A., and Barlati, S. (2000) Cytogenet. Cell Genet., 88, 236–239.PubMedCrossRefGoogle Scholar
  39. 39.
    Herb, A., Higuchi, M., Sprengel, R., and Seeburg, P. H. (1996) Proc. Natl. Acad. Sci. USA, 93, 1875–1880.PubMedCrossRefGoogle Scholar
  40. 40.
    Barbon, A., Vallini, I., and Barlati, S. (2001) Gene, 274, 187–197.PubMedCrossRefGoogle Scholar
  41. 41.
    Burnashev, N., Zhou, Z., Neher, E., and Sakmann, B. (1995) J. Physiol., 485, 403–418.PubMedGoogle Scholar
  42. 42.
    Belcher, S. M., and Howe, J. R. (1997) Brain Res. Mol. Brain Res., 52, 130–138.PubMedCrossRefGoogle Scholar
  43. 43.
    Paschen, W., Schmitt, J., Gissel, C., and Dux, E. (1997) Brain Res. Dev. Brain Res., 98, 271–280.PubMedCrossRefGoogle Scholar
  44. 44.
    Barbon, A., Vallini, I., La Via, L., Marchina, E., and Barlati, S. (2003) Brain Res. Mol. Brain Res., 117, 168–178.PubMedCrossRefGoogle Scholar
  45. 45.
    Bernard, A., Ferhat, L., Dessi, F., Charton, G., Represa, A., Ben-Ari, Y., and Khrestchatisky, M. (1999) Eur. J. Neurosci., 11, 604–616.PubMedCrossRefGoogle Scholar
  46. 46.
    Kohler, M., Burnashev, N., Sakmann, B., and Seeburg, P. H. (1993) Neuron, 10, 491–500.PubMedCrossRefGoogle Scholar
  47. 47.
    Vissel, B., Royle, G. A., Christie, B. R., Schiffer, H. H., Ghetti, A., Tritto, T., Perez-Otano, I., Radcliffe, R. A., Seamans, J., Sejnowski, T., Wehner, J. M., Collins, A. C., O’Gorman, S., and Heinemann, S. F. (2001) Neuron, 29, 217–227.PubMedCrossRefGoogle Scholar
  48. 48.
    Bowie, D., and Mayer, M. L. (1995) Neuron, 15, 453–462.PubMedCrossRefGoogle Scholar
  49. 49.
    Lee, C. J., Kong, H., Manzini, M. C., Albuquerque, C., Chao, M. V., and MacDermott, A. B. (2001) J. Neurosci., 21, 4572–4581.PubMedGoogle Scholar
  50. 50.
    Wilding, T. J., Zhou, Y., and Huettner, J. E. (2005) J. Neurosci., 25, 9470–9478.PubMedCrossRefGoogle Scholar
  51. 51.
    Wilding, T. J., Chen, K., and Huettner, J. E. (2010) J. Gen. Physiol., 136, 339–352.PubMedCrossRefGoogle Scholar
  52. 52.
    Wilding, T. J., Fulling, E., Zhou, Y., and Huettner, J. E. (2008) J. Gen. Physiol., 132, 85–99.PubMedCrossRefGoogle Scholar
  53. 53.
    Sailer, A., Swanson, G. T., Perez-Otano, I., O’Leary, L., Malkmus, S. A., Dyck, R. H., Dickinson-Anson, H., Schiffer, H. H., Maron, C., Yaksh, T. L., Gage, F. H., O’Gorman, S., and Heinemann, S. F. (1999) J. Neurosci., 19, 8757–8764.PubMedGoogle Scholar
  54. 54.
    Ball, S. M., Atlason, P. T., Shittu-Balogun, O. O., and Molnar, E. (2010) J. Neurochem., 114, 1805–1818.PubMedCrossRefGoogle Scholar
  55. 55.
    Ma-Hogemeier, Z. L., Korber, C., Werner, M., Racine, D., Muth-Kohne, E., Tapken, D., and Hollmann, M. (2010) J. Neurochem., 113, 1403–1415.PubMedGoogle Scholar
  56. 56.
    Kawahara, Y., Ito, K., Sun, H., Ito, M., Kanazawa, I., and Kwak, S. (2004) Brain Res. Dev. Brain Res., 148, 151–155.PubMedCrossRefGoogle Scholar
  57. 57.
    Maas, S., Patt, S., Schrey, M., and Rich, A. (2001) Proc. Natl. Acad. Sci. USA, 98, 14687–14692.PubMedCrossRefGoogle Scholar
  58. 58.
    Cenci, C., Barzotti, R., Galeano, F., Corbelli, S., Rota, R., Massimi, L., Di Rocco, C., O’Connell, M. A., and Gallo, A. (2008) J. Biol. Chem., 283, 7251–7260.PubMedCrossRefGoogle Scholar
  59. 59.
    Ishiuchi, S., Yoshida, Y., Sugawara, K., Aihara, M., Ohtani, T., Watanabe, T., Saito, N., Tsuzuki, K., Okado, H., Miwa, A., Nakazato, Y., and Ozawa, S. (2007) J. Neurosci., 27, 7987–8001.PubMedCrossRefGoogle Scholar
  60. 60.
    Gallo, A., and Galardi, S. (2008) RNA Biol., 5, 135–139.PubMedCrossRefGoogle Scholar
  61. 61.
    Peng, P. L., Zhong, X., Tu, W., Soundarapandian, M. M., Molner, P., Zhu, D., Lau, L., Liu, S., Liu, F., and Lu, Y. (2006) Neuron, 49, 719–733.PubMedCrossRefGoogle Scholar
  62. 62.
    Bowie, D. (2008) CNS Neurol. Disord. Drug Targets, 7, 129–143.PubMedCrossRefGoogle Scholar
  63. 63.
    Izzi, C., Barbon, A., Kretz, R., Sander, T., and Barlati, S. (2002) Am. J. Med. Genet., 114, 354–359.PubMedCrossRefGoogle Scholar
  64. 64.
    Grigorenko, E. V., Bell, W. L., Glazier, S., Pons, T., and Deadwyler, S. (1998) Neuroreport, 9, 2219–2224.PubMedCrossRefGoogle Scholar
  65. 65.
    Kortenbruck, G., Berger, E., Speckmann, E. J., and Musshoff, U. (2001) Neurobiol. Dis., 8, 459–468.PubMedCrossRefGoogle Scholar
  66. 66.
    Vollmar, W., Gloger, J., Berger, E., Kortenbruck, G., Kohling, R., Speckmann, E. J., and Musshoff, U. (2004) Neurobiol. Dis., 15, 371–379.PubMedCrossRefGoogle Scholar
  67. 67.
    Magri, C., Gardella, R., Barlati, S. D., Podavini, D., Iatropoulos, P., Bonomi, S., Valsecchi, P., Sacchetti, E., and Barlati, S. (2006) Am. J. Med. Genet. B Neuropsychiatr. Genet., 141B, 287–293.PubMedCrossRefGoogle Scholar
  68. 68.
    Magri, C., Gardella, R., Valsecchi, P., Barlati, S. D., Guizzetti, L., Imperadori, L., Bonvicini, C., Tura, G. B., Gennarelli, M., Sacchetti, E., and Barlati, S. (2008) Am. J. Med. Genet. B Neuropsychiatr. Genet., 147B, 745–753.PubMedCrossRefGoogle Scholar
  69. 69.
    Akbarian, S., Smith, M. A., and Jones, E. G. (1995) Brain Res., 699, 297–304.PubMedCrossRefGoogle Scholar
  70. 70.
    Barbon, A., Fumagalli, F., La Via, L., Caracciolo, L., Racagni, G., Riva, M. A., and Barlati, S. (2007) Exp. Neurol., 208, 54–62.PubMedCrossRefGoogle Scholar
  71. 71.
    Iwamoto, K., Bundo, M., and Kato, T. (2009) RNA Biol., 6, 248–253.PubMedCrossRefGoogle Scholar
  72. 72.
    Barbon, A., Popoli, M., La Via, L., Moraschi, S., Vallini, I., Tardito, D., Tiraboschi, E., Musazzi, L., Giambelli, R., Gennarelli, M., Racagni, G., and Barlati, S. (2006) Biol. Psychiatry, 59, 713–720.PubMedCrossRefGoogle Scholar
  73. 73.
    Sawada, J., Yamashita, T., Aizawa, H., Aburakawa, Y., Hasebe, N., and Kwak, S. (2009) Neurosci. Res., 64, 251–258.PubMedCrossRefGoogle Scholar
  74. 74.
    Kawahara, Y., Ito, K., Sun, H., Aizawa, H., Kanazawa, I., and Kwak, S. (2004) Nature, 427, 801.PubMedCrossRefGoogle Scholar
  75. 75.
    Kwak, S., and Kawahara, Y. (2005) J. Mol. Med., 83, 110–120.PubMedCrossRefGoogle Scholar
  76. 76.
    Hideyama, T., Yamashita, T., Suzuki, T., Tsuji, S., Higuchi, M., Seeburg, P. H., Takahashi, R., Misawa, H., and Kwak, S. (2010) J. Neurosci., 30, 11917–11925.PubMedCrossRefGoogle Scholar
  77. 77.
    Barbon, A., Fumagalli, F., Caracciolo, L., Madaschi, L., Lesma, E., Mora, C., Carelli, S., Slotkin, T. A., Racagni, G., Di Giulio, A. M., Gorio, A., and Barlati, S. (2010) J. Neurochem., 114, 397–407.PubMedGoogle Scholar
  78. 78.
    Frigon, A., and Rossignol, S. (2006) Prog. Brain Res., 157, 231–260.PubMedCrossRefGoogle Scholar
  79. 79.
    Choi, D. W. (1994) Prog. Brain Res., 100, 47–51.PubMedCrossRefGoogle Scholar
  80. 80.
    Michaelis, E. K. (1998) Prog. Neurobiol., 54, 369–415.PubMedCrossRefGoogle Scholar
  81. 81.
    Enstero, M., Akerborg, O., Lundin, D., Wang, B., Furey, T. S., Ohman, M., and Lagergren, J. (2010) BMC Bioinformatics, 11, 6.PubMedCrossRefGoogle Scholar
  82. 82.
    Li, J. B., Levanon, E. Y., Yoon, J. K., Aach, J., Xie, B., Leproust, E., Zhang, K., Gao, Y., and Church, G. M. (2009) Science, 324, 1210–1213.PubMedCrossRefGoogle Scholar
  83. 83.
    Mattick, J. S., and Mehler, M. F. (2008) Trends Neurosci., 31, 227–233.PubMedCrossRefGoogle Scholar
  84. 84.
    Nishikura, K. (2006) Nat. Rev. Mol. Cell Biol., 7, 919–931.PubMedCrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2011

Authors and Affiliations

  1. 1.Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnologies and National Institute of NeuroscienceUniversity of BresciaBresciaItaly

Personalised recommendations