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PIP5K2A-dependent regulation of excitatory amino acid transporter EAAT3

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Abstract

Introduction

According to previous observations, the gene encoding the phosphatidylinositol-4-phosphate 5-kinase II alpha (PIP5K2A) is associated with schizophrenia. Specifically, the mutation N251SPIP5K2A has been discovered in schizophrenic patients but not in healthy individuals. A defect of the excitatory amino acid transporter EAAT3 has similarly been implicated in the development of schizophrenia. The present study thus explored whether PIP5K2A is involved in the regulation of EAAT3 activity.

Materials and methods

EAAT3 was expressed in Xenopus oocytes either without or with PIP5K2A, and EAAT3 transporter activity was estimated from the glutamate (2-mM)-induced current (Iglu) in dual electrode voltage clamp experiments. EAAT3 protein abundance in the cell membrane was estimated by Western blotting and confocal microscopy.

Results

In EAAT3-expressing oocytes, Iglu was enhanced by coexpression of wild type PIP5K2A. Coexpression of the schizophrenia-associated mutant N251SPIP5K2A significantly decreased Iglu in oocytes expressing EAAT3 with or without additional expression of wild type PIP5K2A. Thus, N251SPIP5K2A exerts a dominant inhibitory effect.

Discussion

Membrane abundance of EAAT3 was increased by wild type PIP5K2A and decreased by N251SPIP5K2A in both EAAT3-expressing oocytes and human embryonic kidney cells. The present observations disclose a novel mechanism of EAAT3 regulation, which may contribute to the deranged regulation of excitability in schizophrenic patients.

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Acknowledgements

The authors acknowledge the technical support by Darina Iskalieva and the meticulous preparation of the manuscript by Sari Rübe and Lejla Subasic. This study was supported by the Deutsche Forschungsgemeinschaft, Nr. La 315/6-1, La 315/13-1, and GRK1302.

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Authors and Affiliations

  1. Department of Physiology, University of Tuebingen, Gmelinstr. 5, 72076, Tuebingen, Germany

    Olga Fedorenko, Cai Tang, Mentor Sopjani, Michael Föller, Eva-Maria Gehring, Nathalie Strutz-Seebohm, Oana N. Ureche, Florian Lang & Guiscard Seebohm

  2. Mental Health Research Institute, Sosnovy Bor, 634014, Tomsk, Russia

    Olga Fedorenko, Svetlana Ivanova & Arkadij Semke

  3. Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany

    Undine E. Lang

  4. Cation Channel Group, Ruhr-University Bochum, Universitätsstr. 150, Bochum, Germany

    Nathalie Strutz-Seebohm & Guiscard Seebohm

Authors
  1. Olga Fedorenko
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  2. Cai Tang
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  3. Mentor Sopjani
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  4. Michael Föller
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  7. Oana N. Ureche
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  8. Svetlana Ivanova
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  9. Arkadij Semke
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  10. Florian Lang
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  12. Undine E. Lang
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Correspondence to Florian Lang.

Additional information

Olga Fedorenko and Cai Tang contributed equally and thus share first authorship.

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Fedorenko, O., Tang, C., Sopjani, M. et al. PIP5K2A-dependent regulation of excitatory amino acid transporter EAAT3. Psychopharmacology 206, 429–435 (2009). https://doi.org/10.1007/s00213-009-1621-5

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  • DOI: https://doi.org/10.1007/s00213-009-1621-5

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