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Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1

Nature Neuroscience volume 14, pages 866–873 (2011)Cite this article

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Abstract

Ionotropic glutamate receptors principally mediate fast excitatory transmission in the brain. Among the three classes of ionotropic glutamate receptors, kainate receptors (KARs) have a unique brain distribution, which has been historically defined by 3H-radiolabeled kainate binding. Compared with recombinant KARs expressed in heterologous cells, synaptic KARs exhibit characteristically slow rise-time and decay kinetics. However, the mechanisms responsible for these distinct KAR properties remain unclear. We found that both the high-affinity binding pattern in the mouse brain and the channel properties of native KARs are determined by the KAR auxiliary subunit Neto1. Through modulation of agonist binding affinity and off-kinetics of KARs, but not trafficking of KARs, Neto1 determined both the KAR high-affinity binding pattern and the distinctively slow kinetics of postsynaptic KARs. By regulating KAR excitatory postsynaptic current kinetics, Neto1 can control synaptic temporal summation, spike generation and fidelity.

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Figure 1: Hippocampus-abundant Neto1 interacts with KARs in vivo.
Figure 2: Neto 1 is highly expressed in the hippocampus CA3 pyramidal neurons and localizes at stratum lucidum.
Figure 3: Distinct distribution of high-affinity KARs is determined by Neto1 postsynaptically.
Figure 4: Neto1 modulates KAR function in the hippocampus.
Figure 5: The slow decay of KAR-mediated synaptic transmission is determined by Neto1.
Figure 6: Localization of KARs in the brain is independent of Neto1 and its PDZ-binding domain.
Figure 7: Neto1 modulates KAR-driven temporal summation and spike fidelity in CA3 pyramidal neurons.

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Acknowledgements

We thank members of the Tomita and Castillo laboratories for helpful discussions. We thank M.T.W. Ho for technical advice on slice preparation, G. Somers for maintaining mouse colonies, S.F. Heinemann (Salk Institute) for generating GluK2 knockout mice and the KOMP for creating Neto1 KO mice. S.T. and P.E.C. are supported by grants from the US National Institutes of Health/National Institute of Mental Health (R01 MH085080 and R01 MH081935, respectively). C.S. is supported by a Boehringer-Ingelheim PhD fellowship. M.W. is supported by Grants-in-Aid for Scientific Research (19100005) provided by the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Author notes

  1. Christoph Straub and David L Hunt: These authors contributed equally to this work.

Authors and Affiliations

  1. Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut, USA

    Christoph Straub, Kwang S Kim & Susumu Tomita

  2. Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Christoph Straub, Kwang S Kim & Susumu Tomita

  3. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA

    David L Hunt & Pablo E Castillo

  4. Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Miwako Yamasaki & Masahiko Watanabe

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Contributions

S.T. and P.E.C. conceived the project and wrote the manuscript. C.S., D.L.H., M.Y., K.S.K., M.W. and S.T. performed all of the experiments and analyzed results. All of the authors, C.S. and D.L.H. in particular, contributed to the final version of the manuscript.

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Correspondence to Pablo E Castillo or Susumu Tomita.

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Straub, C., Hunt, D., Yamasaki, M. et al. Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1. Nat Neurosci 14, 866–873 (2011). https://doi.org/10.1038/nn.2837

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