Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Dancing partners at the synapse: auxiliary subunits that shape kainate receptor function

Nature Reviews Neuroscience volume 13, pages 675–686 (2012)Cite this article

Subjects

Key Points

  • Kainate receptors are a family of glutamate-gated ion channels that have diverse roles in modulating both excitatory and inhibitory neurotransmission from a variety of pre- and postsynaptic sites throughout the brain. Postsynaptic kainate receptor currents exhibit small amplitudes but very slow decay kinetics, allowing them to contribute substantially to temporal integration during high-frequency bursts of synaptic input.

  • Approaches using gene-targeting strategies and recombinant expression systems have been unable to identify the specific receptor subunit combinations responsible for the unusual kinetics of kainate receptors observed at synapses throughout the brain.

  • A family of CUB (complement C1R/C1s, Uegf and Bmp1) domain-containing transmembrane proteins comprising neuropilin and tolloid-like 1 (NETO1) and NETO2 were found to alter the functional properties of recombinant kainate receptors to more closely resemble those found in the CNS.

  • These newly identified kainate receptor auxiliary subunits are structurally distinct from those that modulate AMPA receptor function, including transmembrane AMPA receptor regulatory proteins, cornichons and CKAMP44 (cystine-knot AMPAR modulating protein of 44 kDa), and are more closely related to the invertebrate protein SOL-1, an auxiliary subunit of ionotropic glutamate receptors in the nematode Caenorhabditis elegans.

  • NETO1 and NETO2 co-assemble with kainate receptors to modulate a broad array of biophysical properties, including agonist affinity and efficacy, open channel probability, deactivation kinetics and rate of entry into and out of desensitization. Additionally, NETO2 promotes the forward trafficking and synaptic targeting of GluK1-containing receptors.

  • Genetic ablation of Neto1, but not Neto2, demonstrates that this auxiliary subunit co-assembles with postsynaptic kainate receptors in the hippocampus and has an essential role in mediating the slow synaptic current decay observed at this synapse without influencing measures of presynaptic activity.

Abstract

Kainate receptors are a family of ionotropic glutamate receptors whose physiological roles differ from those of other subtypes of glutamate receptors in that they predominantly serve as modulators, rather than mediators, of synaptic transmission. Neuronal kainate receptors exhibit unusually slow kinetic properties that have been difficult to reconcile with the behaviour of recombinant kainate receptors. Recently, however, the neuropilin and tolloid-like 1 (NETO1) and NETO2 proteins were identified as auxiliary kainate receptor subunits that shape both the biophysical properties and synaptic localization of these receptors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Distinctive features of synaptic kainate receptors.
Figure 2: Neuropilin and tolloid-like protein co-assembly alters the biophysical properties of kainate receptors.
Figure 3: Gene-targeting of Neto1 alters synaptic kainate receptor function.

Similar content being viewed by others

References

  1. Contractor, A., Mulle, C. & Swanson, G. T. Kainate receptors coming of age: milestones of two decades of research. Trends Neurosci. 34, 154–163 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chittajallu, R. et al. Regulation of glutamate release by presynaptic kainate receptors in the hippocampus. Nature 379, 78–81 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Castillo, P. E., Malenka, R. C. & Nicoll, R. A. Kainate receptors mediate a slow postsynaptic current in hippocampal CA3 neurons. Nature 388, 182–186 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Vignes, M. & Collingridge, G. L. The synaptic activation of kainate receptors. Nature 388, 179–182 (1997). This study, with reference 3, first described postsynaptic currents mediated by kainate receptors, which were found at hippocampal mossy fibre–CA3 pyramidal cell synapses. The observed currents exhibited remarkably slow kinetics that were incongruous with the gating behaviour of recombinant kainate receptors.

    Article  CAS  PubMed  Google Scholar 

  5. Zhang, W. et al. A transmembrane accessory subunit that modulates kainate-type glutamate receptors. Neuron 61, 385–396 (2009). This study was the first to identify the NETO proteins as potential auxiliary subunits that had a profound impact on kainate receptor functional properties.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Copits, B. A., Robbins, J. S., Frausto, S. & Swanson, G. T. Synaptic targeting and functional modulation of GluK1 kainate receptors by the auxiliary neuropilin and tolloid-like (Neto) proteins. J. Neurosci. 31, 7334–7340 (2011). This study was the first to report a role for NETO proteins in the trafficking and synaptic targeting of kainate receptors. Additionally, NETO1 and NETO2 co-assembly was found to have a bidirectional effect on GluK1 receptor function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Straub, C. et al. Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1. Nature Neurosci. 14, 866–873 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Straub, C., Zhang, W. & Howe, J. R. Neto2 modulation of kainate receptors with different subunit compositions. J. Neurosci. 31, 8078–8082 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tang, M. et al. Neto1 Is an auxiliary subunit of native synaptic kainate receptors. J. Neurosci. 31, 10009–10018 (2011). This report and the report in reference 7 demonstrated that NETO1 confers slow gating kinetics on postsynaptic kainate receptors at the hippocampal mossy fibre synapse, thereby providing key evidence that it is an auxiliary protein for kainate receptors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jackson, A. C. & Nicoll, R. A. The expanding social network of ionotropic glutamate receptors: TARPs and other transmembrane auxiliary subunits. Neuron 70, 178–199 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Vacher, H., Mohapatra, D. P. & Trimmer, J. S. Localization and targeting of voltage-dependent ion channels in mammalian central neurons. Physiol. Rev. 88, 1407–1447 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Straub, C. & Tomita, S. The regulation of glutamate receptor trafficking and function by TARPs and other transmembrane auxiliary subunits. Curr. Opin. Neurobiol. 22, 488–495 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Hollmann, M. & Heinemann, S. Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Agrawal, S. G. & Evans, R. H. The primary afferent depolarizing action of kainate in the rat. Br. J. Pharmacol. 87, 345–355 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Huettner, J. E. Glutamate receptor channels in rat DRG neurons: activation by kainate and quisqualate and blockade of desensitization by Con A. Neuron 5, 255–266 (1990).

    Article  CAS  PubMed  Google Scholar 

  16. Lerma, J., Paternain, A. V., Naranjo, J. R. & Mellstrom, B. Functional kainate-selective glutamate receptors in cultured hippocampal neurons. Proc. Natl Acad. Sci. USA 90, 11688–11692 (1993). These authors, for the first time, recorded pharmacologically isolated kainate receptor-mediated currents from neurons derived from the CNS using a newly developed non-competitive AMPA receptor antagonist, thereby setting the stage for subsequent detection of postsynaptic kainate receptors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Traynelis, S. F. et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62, 405–496 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jane, D. E., Lodge, D. & Collingridge, G. L. Kainate receptors: pharmacology, function and therapeutic potential. Neuropharmacology 56, 90–113 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Heckmann, M., Bufler, J., Franke, C. & Dudel, J. Kinetics of homomeric GluR6 glutamate receptor channels. Biophys. J. 71, 1743–1750 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Traynelis, S. F. & Wahl, P. Control of rat GluR6 glutamate receptor open probability by protein kinase A and calcineurin. J. Physiol. 503, 513–531 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Swanson, G. T. & Heinemann, S. F. Heterogeneity of homomeric GluR5 kainate receptor desensitization expressed in HEK293 cells. J. Physiol. 513, 639–646 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bowie, D. & Lange, G. D. Functional stoichiometry of glutamate receptor desensitization. J. Neurosci. 22, 3392–3403 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Paternain, A. V., Cohen, A., Stern-Bach, Y. & Lerma, J. A role for extracellular Na+ in the channel gating of native and recombinant kainate receptors. J. Neurosci. 23, 8641–8648 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wong, A. Y., Fay, A. M. & Bowie, D. External ions are coactivators of kainate receptors. J. Neurosci. 26, 5750–5755 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Plested, A. J. & Mayer, M. L. Structure and mechanism of kainate receptor modulation by anions. Neuron 53, 829–841 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Plested, A. J., Vijayan, R., Biggin, P. C. & Mayer, M. L. Molecular basis of kainate receptor modulation by sodium. Neuron 58, 720–735 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bowie, D. Ion-dependent gating of kainate receptors. J. Physiol. 588, 67–81 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Paternain, A. V., Morales, M. & Lerma, J. Selective antagonism of AMPA receptors unmasks kainate receptor-mediated responses in hippocampal neurons. Neuron 14, 185–189 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Pinheiro, P. S. et al. Selective block of postsynaptic kainate receptors reveals their function at hippocampal mossy fiber synapses. Cereb. Cortex 17 Feb 2012 (doi:10.1093/cercor/bhs022).

  30. Frerking, M. & Ohliger-Frerking, P. AMPA receptors and kainate receptors encode different features of afferent activity. J. Neurosci. 22, 7434–7443 (2002). This report laid experimental and theoretical groundwork for the now prevalent concept that postsynaptic AMPA and kainate receptors have distinct roles in synaptic integration as a result of their divergent gating kinetics.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cossart, R., Esclapez, M., Hirsch, J. C., Bernard, C. & Ben-Ari, Y. GluR5 kainate receptor activation in interneurons increases tonic inhibition of pyramidal cells. Nature Neurosci. 1, 470–478 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Frerking, M., Malenka, R. C. & Nicoll, R. A. Synaptic activation of kainate receptors on hippocampal interneurons. Nature Neurosci. 1, 479–486 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Kidd, F. L. & Isaac, J. T. Developmental and activity-dependent regulation of kainate receptors at thalamocortical synapses. Nature 400, 569–573 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Li, P. et al. Kainate-receptor-mediated sensory synaptic transmission in mammalian spinal cord. Nature 397, 161–164 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Petralia, R. S., Wang, Y. X. & Wenthold, R. J. Histological and ultrastructural localization of the kainate receptor subunits, KA2 and GluR6/7, in the rat nervous system using selective antipeptide antibodies. J. Comp. Neurol. 349, 85–110 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Min, M. Y., Rusakov, D. A. & Kullmann, D. M. Activation of AMPA, kainate, and metabotropic receptors at hippocampal mossy fiber synapses: role of glutamate diffusion. Neuron 21, 561–570 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Kidd, F. L. & Isaac, J. T. Kinetics and activation of postsynaptic kainate receptors at thalamocortical synapses: role of glutamate clearance. J. Neurophysiol. 86, 1139–1148 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Darstein, M., Petralia, R. S., Swanson, G. T., Wenthold, R. J. & Heinemann, S. F. Distribution of kainate receptor subunits at hippocampal mossy fiber synapses. J. Neurosci. 23, 8013–8019 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Herb, A. et al. The KA-2 subunit of excitatory amino acid receptors shows widespread expression in brain and forms ion channels with distantly related subunits. Neuron 8, 775–785 (1992).

    Article  CAS  PubMed  Google Scholar 

  40. Schiffer, H. H., Swanson, G. T. & Heinemann, S. F. Rat GluR7 and a carboxy-terminal splice variant, GluR7b, are functional kainate receptor subunits with a low sensitivity to glutamate. Neuron 19, 1141–1146 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Swanson, G. T., Gereau, R. W., Green, T. & Heinemann, S. F. Identification of amino acid residues that control functional behavior in GluR5 and GluR6 kainate receptors. Neuron 19, 913–926 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Cui, C. & Mayer, M. L. Heteromeric kainate receptors formed by the coassembly of GluR5, GluR6, and GluR7. J. Neurosci. 19, 8281–8291 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Paternain, A. V., Herrera, M. T., Nieto, M. A. & Lerma, J. GluR5 and GluR6 kainate receptor subunits coexist in hippocampal neurons and coassemble to form functional receptors. J. Neurosci. 20, 196–205 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Barberis, A., Sachidhanandam, S. & Mulle, C. GluR6/KA2 kainate receptors mediate slow-deactivating currents. J. Neurosci. 28, 6402–6406 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mulle, C. et al. Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice. Nature 392, 601–605 (1998). This was the first study to use gene-targeting to investigate neuronal kainate receptor function. The authors found that the GluK2 (GluR6) subunit was an essential constituent of postsynaptic kainate receptors in the CA3 region of hippocampus.

    Article  CAS  PubMed  Google Scholar 

  46. Contractor, A. et al. Loss of kainate receptor-mediated heterosynaptic facilitation of mossy-fiber synapses in KA2−/− mice. J. Neurosci. 23, 422–429 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fernandes, H. B. et al. High-affinity kainate receptor subunits are necessary for ionotropic but not metabotropic signaling. Neuron 63, 818–829 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schmitz, D., Frerking, M. & Nicoll, R. A. Synaptic activation of presynaptic kainate receptors on hippocampal mossy fiber synapses. Neuron 27, 327–338 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Contractor, A., Swanson, G. T. & Heinemann, S. F. Kainate receptors are involved in short and long term plasticity at mossy fiber synapses in the hippocampus. Neuron 29, 209–216 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Pinheiro, P. S. et al. GluR7 is an essential subunit of presynaptic kainate autoreceptors at hippocampal mossy fiber synapses. Proc. Natl Acad. Sci. USA 104, 12181–12186 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cossart, R. et al. Presynaptic kainate receptors that enhance the release of GABA on CA1 hippocampal interneurons. Neuron 29, 497–508 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Delaney, A. J. & Jahr, C. E. Kainate receptors differentially regulate release at two parallel fiber synapses. Neuron 36, 475–482 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Huang, Y. H., Dykes-Hoberg, M., Tanaka, K., Rothstein, J. D. & Bergles, D. E. Climbing fiber activation of EAAT4 transporters and kainate receptors in cerebellar Purkinje cells. J. Neurosci. 24, 103–111 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rodríguez-Moreno, A. & Lerma, J. Kainate receptor modulation of GABA release involves a metabotropic function. Neuron 20, 1211–1218 (1998). This study introduces the concept of metabotropic signalling by kainate receptors acting as heterosynaptic modulators of GABA release in the CA1 region.

    Article  PubMed  Google Scholar 

  55. Melyan, Z., Wheal, H. V. & Lancaster, B. Metabotropic-mediated kainate receptor regulation of IsAHP and excitability in pyramidal cells. Neuron 34, 107–114 (2002). These authors demonstrated that kainate receptors regulate intrinsic conductances in CA1 pyramidal neurons through G protein-mediated signalling pathways.

    Article  CAS  PubMed  Google Scholar 

  56. Melyan, Z., Lancaster, B. & Wheal, H. V. Metabotropic regulation of intrinsic excitability by synaptic activation of kainate receptors. J. Neurosci. 24, 4530–4534 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Fisahn, A., Heinemann, S. F. & McBain, C. J. The kainate receptor subunit GluR6 mediates metabotropic regulation of the slow and medium AHP currents in mouse hippocampal neurones. J. Physiol. 562, 199–203 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Ruiz, A., Sachidhanandam, S., Utvik, J. K., Coussen, F. & Mulle, C. Distinct subunits in heteromeric kainate receptors mediate ionotropic and metabotropic function at hippocampal mossy fiber synapses. J. Neurosci. 25, 11710–11718 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Coussen, F. Molecular determinants of kainate receptor trafficking. Neuroscience 158, 25–35 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Garcia, E. P. et al. SAP90 binds and clusters kainate receptors causing incomplete desensitization. Neuron 21, 727–739 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Bowie, D., Garcia, E. P., Marshall, J., Traynelis, S. F. & Lange, G. D. Allosteric regulation and spatial distribution of kainate receptors bound to ancillary proteins. J. Physiol. 547, 373–385 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hirbec, H. et al. Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP. Neuron 37, 625–638 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Selak, S. et al. A role for SNAP25 in internalization of kainate receptors and synaptic plasticity. Neuron 63, 357–371 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Coussen, F. et al. Recruitment of the kainate receptor subunit glutamate receptor 6 by cadherin/catenin complexes. J. Neurosci. 22, 6426–6436 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Vivithanaporn, P., Yan, S. & Swanson, G. T. Intracellular trafficking of KA2 kainate receptors mediated by interactions with coatomer protein complex I (COPI) and 14-3-3 chaperone systems. J. Biol. Chem. 281, 15475–15484 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Salinas, G. D. et al. Actinfilin is a CUL3 substrate adaptor, linking GluR6 kainate receptor subunits to the ubiquitin-proteasome pathway. J. Biol. Chem. 281, 40164–40173 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Newpher, T. M. & Ehlers, M. D. Glutamate receptor dynamics in dendritic microdomains. Neuron 58, 472–497 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Laezza, F. et al. KRIP6: a novel BTB/kelch protein regulating function of kainate receptors. Mol. Cell. Neurosci. 34, 539–550 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ng, D. et al. Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. PLoS Biol. 7, e41 (2009).

    PubMed  Google Scholar 

  70. Stöhr, H., Berger, C., Fröhlich, S. & Weber, B. H. A novel gene encoding a putative transmembrane protein with two extracellular CUB domains and a low-density lipoprotein class A module: isolation of alternatively spliced isoforms in retina and brain. Gene 286, 223–231 (2002).

    Article  PubMed  Google Scholar 

  71. Michishita, M. et al. A novel gene, Btcl1, encoding CUB and LDLa domains is expressed in restricted areas of mouse brain. Biochem. Biophys. Res. Commun. 306, 680–686 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Michishita, M. et al. Expression of Btcl2, a novel member of Btcl gene family, during development of the central nervous system. Dev. Brain. Res. 153, 135–142 (2004).

    Article  CAS  Google Scholar 

  73. Bork, P. & Beckmann, G. The CUB domain: a widespread module in developmentally regulated proteins. J. Mol. Biol. 231, 539–545 (1993).

    Article  CAS  PubMed  Google Scholar 

  74. He, Z. & Tessier-Lavigne, M. Neuropilin is a receptor for the axonal chemorepellent semaphorin III. Cell 90, 739–751 (1997).

    Article  CAS  PubMed  Google Scholar 

  75. Kolodkin, A. L. et al. Neuropilin is a semaphorin III receptor. Cell 90, 753–762 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Gally, C., Eimer, S., Richmond, J. E. & Bessereau, J. L. A transmembrane protein required for acetylcholine receptor clustering in Caenorhabditis elegans. Nature 431, 578–582 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zheng, Y., Mellem, J. E., Brockie, P. J., Madsen, D. M. & Maricq, A. V. SOL-1 is a CUB-domain protein required for GLR-1 glutamate receptor function in C. elegans. Nature 427, 451–457 (2004). This study reports the first CUB domain-containing auxiliary subunit for iGluRs, SOL-1, using a forward genetic screen in C. elegans.

    Article  CAS  PubMed  Google Scholar 

  78. Zheng, Y. et al. SOL-1 is an auxiliary subunit that modulates the gating of GLR-1 glutamate receptors in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 103, 1100–1105 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Yan, D. & Tomita, S. Defined criteria for auxiliary subunits of glutamate receptors. J. Physiol. 590, 21–31 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Kim, Y. J., Bao, H., Bonanno, L., Zhang, B. & Serpe, M. Drosophila Neto is essential for clustering glutamate receptors at the neuromuscular junction. Genes Dev. 26, 974–987 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Jaskolski, F. et al. Subunit composition and alternative splicing regulate membrane delivery of kainate receptors. J. Neurosci. 24, 2506–2515 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yan, S. et al. A C-terminal determinant of GluR6 kainate receptor trafficking. J. Neurosci. 24, 679–691 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Coussen, F. et al. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex. Neuron 47, 555–566 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Milstein, A. D., Zhou, W., Karimzadegan, S., Bredt, D. S. & Nicoll, R. A. TARP subtypes differentially and dose-dependently control synaptic AMPA receptor gating. Neuron 55, 905–918 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gill, M. B. et al. Cornichon-2 modulates AMPA receptor–transmembrane AMPA receptor regulatory protein assembly to dictate gating and pharmacology. J. Neurosci. 31, 6928–6938 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kato, A. S., Gill, M. B., Yu, H., Nisenbaum, E. S. & Bredt, D. S. TARPs differentially decorate AMPA receptors to specify neuropharmacology. Trends Neurosci. 33, 241–248 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Stern-Bach, Y., Russo, S., Neuman, M. & Rosenmund, C. A point mutation in the glutamate binding site blocks desensitization of AMPA receptors. Neuron 21, 907–918 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. Sun, Y. et al. Mechanism of glutamate receptor desensitization. Nature 417, 245–253 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Yelshansky, M. V., Sobolevsky, A. I., Jatzke, C. & Wollmuth, L. P. Block of AMPA receptor desensitization by a point mutation outside the ligand-binding domain. J. Neurosci. 24, 4728–4736 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Vivithanaporn, P., Lash, L. L., Marszalec, B. & Swanson, G. T. Critical roles for the M3–S2 transduction linker domain in kainate receptor assembly and postassembly trafficking. J. Neurosci. 27, 10423–10433 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lerma, J. Kainate receptor physiology. Curr. Opin. Pharmacol. 6, 89–97 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Pinheiro, P. S. & Mulle, C. Presynaptic glutamate receptors: physiological functions and mechanisms of action. Nature Rev. Neurosci. 9, 423–436 (2008).

    Article  CAS  Google Scholar 

  93. Kamiya, H. & Ozawa, S. Kainate receptor-mediated presynaptic inhibition at the mouse hippocampal mossy fibre synapse. J. Physiol. 523, 653–665 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lauri, S. E. et al. A role for Ca2+ stores in kainate receptor-dependent synaptic facilitation and LTP at mossy fiber synapses in the hippocampus. Neuron 39, 327–341 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Kwon, H. B. & Castillo, P. E. Role of glutamate autoreceptors at hippocampal mossy fiber synapses. Neuron 60, 1082–1094 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rouach, N. et al. TARP γ-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity. Nature Neurosci. 8, 1525–1533 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Bats, C., Groc, L. & Choquet, D. The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking. Neuron 53, 719–734 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Opazo, P. et al. CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin. Neuron 67, 239–252 (2010).

    Article  CAS  PubMed  Google Scholar 

  99. Cossart, R. et al. Quantal release of glutamate generates pure kainate and mixed AMPA/kainate EPSCs in hippocampal neurons. Neuron 35, 147–159 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. DeVries, S. H. & Schwartz, E. A. Kainate receptors mediate synaptic transmission between cones and 'Off' bipolar cells in a mammalian retina. Nature 397, 157–160 (1999).

    Article  CAS  PubMed  Google Scholar 

  101. DeVries, S. H. Bipolar cells use kainate and AMPA receptors to filter visual information into separate channels. Neuron 28, 847–856 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. DeVries, S. H., Li, W. & Saszik, S. Parallel processing in two transmitter microenvironments at the cone photoreceptor synapse. Neuron 50, 735–748 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Gendrel, M., Rapti, G., Richmond, J. E. & Bessereau, J. L. A secreted complement-control-related protein ensures acetylcholine receptor clustering. Nature 461, 992–996 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Shepherd, J. D. & Huganir, R. L. The cell biology of synaptic plasticity: AMPA receptor trafficking. Ann. Rev. Cell Dev. Biol. 23, 613–643 (2007).

    Article  CAS  Google Scholar 

  105. Anggono, V. & Huganir, R. L. Regulation of AMPA receptor trafficking and synaptic plasticity. Curr. Opin. Neurobiol. 22, 461–469 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Isom, L. L., De Jongh, K. S. & Catterall, W. A. Auxiliary subunits of voltage-gated ion channels. Neuron 12, 1183–1194 (1994).

    Article  CAS  PubMed  Google Scholar 

  107. Arikkath, J. & Campbell, K. P. Auxiliary subunits: essential components of the voltage-gated calcium channel complex. Curr. Opin. Neurobiol. 13, 298–307 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Walker, C. S. et al. Conserved SOL-1 proteins regulate ionotropic glutamate receptor desensitization. Proc. Natl Acad. Sci. USA 103, 10787–10792 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Schwenk, J. et al. Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science 323, 1313–1319 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. von Engelhardt, J. et al. CKAMP44: a brain-specific protein attenuating short-term synaptic plasticity in the dentate gyrus. Science 327, 1518–1522 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Schwenk, J. et al. High-resolution proteomics unravel architecture and molecular diversity of native AMPA receptor complexes. Neuron 74, 621–633 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Shanks, N. F. et al. Differences in AMPA and kainate receptor interactomes faciliate identification of AMPA receptor auxiliary subunit GSG1L. Cell Rep. 1, 590–598 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Yamazaki, M. et al. A novel action of stargazin as an enhancer of AMPA receptor activity. Neurosci. Res. 50, 369–374 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Priel, A. et al. Stargazin reduces desensitization and slows deactivation of the AMPA-type glutamate receptors. J. Neurosci. 25, 2682–2686 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tomita, S. et al. Stargazin modulates AMPA receptor gating and trafficking by distinct domains. Nature 435, 1052–1058 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Turetsky, D., Garringer, E. & Patneau, D. K. Stargazin modulates native AMPA receptor functional properties by two distinct mechanisms. J. Neurosci. 25, 7438–7448 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Menuz, K., Stroud, R. M., Nicoll, R. A. & Hays, F. A. TARP auxiliary subunits switch AMPA receptor antagonists into partial agonists. Science 318, 815–817 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Cho, C.-H., St-Gelais, F., Zhang, W., Tomita, S. & Howe, J. R. Two families of TARP isoforms that have distinct effects on the kinetic properties of AMPA receptors and synaptic currents. Neuron 55, 890–904 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Soto, D. et al. Selective regulation of long-form calcium-permeable AMPA receptors by an atypical TARP, γ-5. Nature Neurosci. 12, 277–285 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Jackson, A. C. et al. Probing TARP modulation of AMPA receptor conductance with polyamine toxins. J. Neurosci. 31, 7511–7520 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Tomita, S. et al. Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins. J. Cell Biol. 161, 805–816 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Bedoukian, M. A., Weeks, A. M. & Partin, K. M. Different domains of the AMPA receptor direct stargazin-mediated trafficking and stargazin-mediated modulation of kinetics. J. Biol. Chem. 281, 23908–23921 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Chen, L. et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Schnell, E. et al. Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proc. Natl Acad. Sci. USA 99, 13902–13907 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Menuz, K., O'Brien, J. L., Karmizadegan, S., Bredt, D. S. & Nicoll, R. A. TARP redundancy is critical for maintaining AMPA receptor function. J. Neurosci. 28, 8740–8746 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Rebola, N., Sachidhanandam, S., Perrais, D., Cunha, R. A. & Mulle, C. Short-term plasticity of kainate receptor-mediated EPSCs induced by NMDA receptors at hippocampal mossy fiber synapses. J. Neurosci. 27, 3987–3993 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank A. Contractor (Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA) for contributing original data to this article and C. Mulle (University of Bordeaux II, Bordeaux, France) for sharing data in advance of its publication. This work was supported by grants R01 NS44322 and R01 NS071952 from the US National Institute of Neurological Disorders and Stroke to G.T.S.

Author information

Authors and Affiliations

  1. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, 60611, Illinois, USA

    Bryan A. Copits & Geoffrey T. Swanson

Authors
  1. Bryan A. Copits
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Geoffrey T. Swanson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Geoffrey T. Swanson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Allen Mouse Brain Atlas

Glossary

Recombinant receptors

Receptors produced subsequent to the introduction into cells of complementary DNA-encoding component receptor subunits.

Desensitization

A decrease in a biological response in the continued presence of or due to repeated exposure of a receptor to an agonist.

Excitatory postsynaptic currents

(EPSCs). Membrane currents arising from activation of excitatory (depolarizing) postsynaptic ligand-gated ion channels by a physiological stimulus, typically measured when membrane potential is held constant in voltage clamp experiments.

Hippocampal mossy fibre

Axons arising from dentate gyrus granule cells that form bouton-type synapses on proximal dendrites of CA3 pyramidal neurons and filopodial synapses on interneurons in the stratum lucidum.

Short-term potentiation

A predominantly presynaptic form of plasticity in which synaptic transmission is transiently enhanced, principally due to the engagement of mechanisms that enhance vesicle release probability.

Chaperone proteins

Proteins that facilitate or are necessary for trafficking of cargo proteins through the secretory pathway in cells, which can include targeting receptors to their pre- or postsynaptic sites of action.

Pertussis toxin

The causative agent of whooping cough, which causes the persistent activation of Gi proteins by catalysing ADP-ribosylation of the Gαi subunit.

SNARE

Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor.

Deactivation

A reduction in a receptor-mediated biological response subsequent to the removal of agonist.

Open probability

The probability that an ion channel protein is in the open state under a given experimental condition.

Open time

The average time an ion channel dwells in a conducting state during a single activation event.

Single-channel conductance

An expression of the rate of ion flow through an ion channel during a single activation event; it is derived from Ohm's Law as a proportionality constant equal to the inverse of resistance.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Copits, B., Swanson, G. Dancing partners at the synapse: auxiliary subunits that shape kainate receptor function. Nat Rev Neurosci 13, 675–686 (2012). https://doi.org/10.1038/nrn3335

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn3335

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing