Abstract
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.
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Chen, M., and Manley, J. L. (2009) Nat. Rev. Mol. Cell Biol., 10, 741–754.
Benne, R., van den Burg, J., Brakenhoff, J. P., Sloof, P., van Boom, J. H., and Tromp, M. C. (1986) Cell, 46, 819–826.
Smith, H. C. (2008) RNA and DNA Editing: Molecular Mechanisms and Their Integration into Biological Systems, Wiley Interscience, Hoboken, NJ, USA.
Farajollahi, S., and Maas, S. (2010) Trends Genet., 26, 221–230.
Bass, B. L. (2002) Ann. Rev. Biochem., 71, 817–846.
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.
Bigge, C. F. (1999) Curr. Opin. Chem. Biol., 3, 441–447.
Dingledine, R., Borges, K., Bowie, D., and Traynelis, S. F. (1999) Pharmacol. Rev., 51, 7–61.
Collingridge, G. L., Olsen, R., Peters, J. A., and Spedding, M. (2009) Neuropharmacology, 56, 2–5.
Wenthold, R. J., Petralia, R. S., Blahos, J., II, and Niedzielski, A. S. (1996) J. Neurosci., 16, 1982–1989.
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.
Lambolez, B., Ropert, N., Perrais, D., Rossier, J., and Hestrin, S. (1996) Proc. Natl. Acad. Sci. USA, 93, 1797–1802.
Hollmann, M., and Heinemann, S. (1994) Ann. Rev. Neurosci., 17, 31–108.
Monyer, H., Seeburg, P. H., and Wisden, W. (1991) Neuron, 6, 799–810.
Pinheiro, P. S., and Mulle, C. (2008) Nat. Rev. Neurosci., 9, 423–436.
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.
Schorge, S., and Colquhoun, D. (2003) J. Neurosci., 23, 1151–1158.
Ulbrich, M. H., and Isacoff, E. Y. (2008) Proc. Natl. Acad. Sci. USA, 105, 14163–14168.
Nishikura, K. (2010) Ann. Rev. Biochem., 79, 321–349.
Egebjerg, J., and Heinemann, S. F. (1993) Proc. Natl. Acad. Sci. USA, 90, 755–759.
Swanson, G. T., Feldmeyer, D., Kaneda, M., and Cull-Candy, S. G. (1996) J. Physiol., 492, 129–142.
Kamboj, S. K., Swanson, G. T., and Cull-Candy, S. G. (1995) J. Physiol., 486, 297–303.
Brusa, R., Zimmermann, F., Koh, D. S., Feldmeyer, D., Gass, P., Seeburg, P. H., and Sprengel, R. (1995) Science, 270, 1677–1680.
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.
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.
Schoft, V. K., Schopoff, S., and Jantsch, M. F. (2007) Nucleic Acids Res., 35, 3723–3732.
Kask, K., Zamanillo, D., Rozov, A., Burnashev, N., Sprengel, R., and Seeburg, P. H. (1998) Proc. Natl. Acad. Sci. USA, 95, 13777–13782.
Whitney, N. P., Peng, H., Erdmann, N. B., Tian, C., Monaghan, D. T., and Zheng, J. C. (2008) FASEB J., 22, 2888–2900.
Greger, I. H., Khatri, L., and Ziff, E. B. (2002) Neuron, 34, 759–772.
Greger, I. H., Khatri, L., Kong, X., and Ziff, E. B. (2003) Neuron, 40, 763–774.
Krampfl, K., Schlesinger, F., Zorner, A., Kappler, M., Dengler, R., and Bufler, J. (2002) Eur. J. Neurosci., 15, 51–62.
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.
Koike, M., Tsukada, S., Tsuzuki, K., Kijima, H., and Ozawa, S. (2000) J. Neurosci., 20, 2166–2174.
Grosskreutz, J., Zoerner, A., Schlesinger, F., Krampfl, K., Dengler, R., and Bufler, J. (2003) Eur. J. Neurosci., 17, 1173–1178.
Laurencikiene, J., Kallman, A. M., Fong, N., Bentley, D. L., and Ohman, M. (2006) EMBO Rep., 7, 303–307.
Ryman, K., Fong, N., Bratt, E., Bentley, D. L., and Ohman, M. (2007) RNA, 13, 1071–1078.
Penn, A. C., and Greger, I. H. (2009) RNA Biol., 6, 517–521.
Barbon, A., and Barlati, S. (2000) Cytogenet. Cell Genet., 88, 236–239.
Herb, A., Higuchi, M., Sprengel, R., and Seeburg, P. H. (1996) Proc. Natl. Acad. Sci. USA, 93, 1875–1880.
Barbon, A., Vallini, I., and Barlati, S. (2001) Gene, 274, 187–197.
Burnashev, N., Zhou, Z., Neher, E., and Sakmann, B. (1995) J. Physiol., 485, 403–418.
Belcher, S. M., and Howe, J. R. (1997) Brain Res. Mol. Brain Res., 52, 130–138.
Paschen, W., Schmitt, J., Gissel, C., and Dux, E. (1997) Brain Res. Dev. Brain Res., 98, 271–280.
Barbon, A., Vallini, I., La Via, L., Marchina, E., and Barlati, S. (2003) Brain Res. Mol. Brain Res., 117, 168–178.
Bernard, A., Ferhat, L., Dessi, F., Charton, G., Represa, A., Ben-Ari, Y., and Khrestchatisky, M. (1999) Eur. J. Neurosci., 11, 604–616.
Kohler, M., Burnashev, N., Sakmann, B., and Seeburg, P. H. (1993) Neuron, 10, 491–500.
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.
Bowie, D., and Mayer, M. L. (1995) Neuron, 15, 453–462.
Lee, C. J., Kong, H., Manzini, M. C., Albuquerque, C., Chao, M. V., and MacDermott, A. B. (2001) J. Neurosci., 21, 4572–4581.
Wilding, T. J., Zhou, Y., and Huettner, J. E. (2005) J. Neurosci., 25, 9470–9478.
Wilding, T. J., Chen, K., and Huettner, J. E. (2010) J. Gen. Physiol., 136, 339–352.
Wilding, T. J., Fulling, E., Zhou, Y., and Huettner, J. E. (2008) J. Gen. Physiol., 132, 85–99.
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.
Ball, S. M., Atlason, P. T., Shittu-Balogun, O. O., and Molnar, E. (2010) J. Neurochem., 114, 1805–1818.
Ma-Hogemeier, Z. L., Korber, C., Werner, M., Racine, D., Muth-Kohne, E., Tapken, D., and Hollmann, M. (2010) J. Neurochem., 113, 1403–1415.
Kawahara, Y., Ito, K., Sun, H., Ito, M., Kanazawa, I., and Kwak, S. (2004) Brain Res. Dev. Brain Res., 148, 151–155.
Maas, S., Patt, S., Schrey, M., and Rich, A. (2001) Proc. Natl. Acad. Sci. USA, 98, 14687–14692.
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.
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.
Gallo, A., and Galardi, S. (2008) RNA Biol., 5, 135–139.
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.
Bowie, D. (2008) CNS Neurol. Disord. Drug Targets, 7, 129–143.
Izzi, C., Barbon, A., Kretz, R., Sander, T., and Barlati, S. (2002) Am. J. Med. Genet., 114, 354–359.
Grigorenko, E. V., Bell, W. L., Glazier, S., Pons, T., and Deadwyler, S. (1998) Neuroreport, 9, 2219–2224.
Kortenbruck, G., Berger, E., Speckmann, E. J., and Musshoff, U. (2001) Neurobiol. Dis., 8, 459–468.
Vollmar, W., Gloger, J., Berger, E., Kortenbruck, G., Kohling, R., Speckmann, E. J., and Musshoff, U. (2004) Neurobiol. Dis., 15, 371–379.
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.
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.
Akbarian, S., Smith, M. A., and Jones, E. G. (1995) Brain Res., 699, 297–304.
Barbon, A., Fumagalli, F., La Via, L., Caracciolo, L., Racagni, G., Riva, M. A., and Barlati, S. (2007) Exp. Neurol., 208, 54–62.
Iwamoto, K., Bundo, M., and Kato, T. (2009) RNA Biol., 6, 248–253.
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.
Sawada, J., Yamashita, T., Aizawa, H., Aburakawa, Y., Hasebe, N., and Kwak, S. (2009) Neurosci. Res., 64, 251–258.
Kawahara, Y., Ito, K., Sun, H., Aizawa, H., Kanazawa, I., and Kwak, S. (2004) Nature, 427, 801.
Kwak, S., and Kawahara, Y. (2005) J. Mol. Med., 83, 110–120.
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.
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.
Frigon, A., and Rossignol, S. (2006) Prog. Brain Res., 157, 231–260.
Choi, D. W. (1994) Prog. Brain Res., 100, 47–51.
Michaelis, E. K. (1998) Prog. Neurobiol., 54, 369–415.
Enstero, M., Akerborg, O., Lundin, D., Wang, B., Furey, T. S., Ohman, M., and Lagergren, J. (2010) BMC Bioinformatics, 11, 6.
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.
Mattick, J. S., and Mehler, M. F. (2008) Trends Neurosci., 31, 227–233.
Nishikura, K. (2006) Nat. Rev. Mol. Cell Biol., 7, 919–931.
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Published in Russian in Biokhimiya, 2011, Vol. 76, No. 8, pp. 1079–1088.
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Barbon, A., Barlati, S. Glutamate receptor RNA editing in health and disease. Biochemistry Moscow 76, 882–889 (2011). https://doi.org/10.1134/S0006297911080037
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DOI: https://doi.org/10.1134/S0006297911080037