Huntingtin-associated protein 1 regulates inhibitory synaptic transmission by modulating γ-aminobutyric acid type A receptor membrane trafficking

August 13, 2004
101 (34) 12736-12741

Abstract

γ-Aminobutyric acid type A receptors (GABAARs) are the major sites of fast synaptic inhibition in the brain. An essential determinant for the efficacy of synaptic inhibition is the regulation of GABAAR cell surface stability. Here, we have examined the regulation of GABAAR endocytic sorting, a critical regulator of cell surface receptor number. In neurons, rapid constitutive endocytosis of GABAARs was evident. Internalized receptors were then either rapidly recycled back to the cell surface, or on a slower time scale, targeted for lysosomal degradation. This sorting decision was regulated by a direct interaction of GABAARs with Huntingtin-associated protein 1 (HAP1). HAP1 modulated synaptic GABAAR number by inhibiting receptor degradation and facilitating receptor recycling. Together these observations have identified a role for HAP1 in regulating GABAAR sorting, suggesting an important role for this protein in the construction and maintenance of inhibitory synapses.

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Acknowledgments

We thank X.-J. Li (Emory University, Atlanta) for the HAP1 expression constructs, P. Worley (The Johns Hopkins University, Baltimore) for the pPC86 Y2H library, and J. M. Fritschy (University of Zurich, Zurich) for the γ2 antibody.

Supporting Information

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Information & Authors

Information

Published in

The cover image for PNAS Vol.101; No.34
Proceedings of the National Academy of Sciences
Vol. 101 | No. 34
August 24, 2004
PubMed: 15310851

Classifications

Submission history

Received: March 16, 2004
Published online: August 13, 2004
Published in issue: August 24, 2004

Acknowledgments

We thank X.-J. Li (Emory University, Atlanta) for the HAP1 expression constructs, P. Worley (The Johns Hopkins University, Baltimore) for the pPC86 Y2H library, and J. M. Fritschy (University of Zurich, Zurich) for the γ2 antibody.

Authors

Affiliations

Josef T. Kittler
Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom; Department of Neuroscience, University of Pennsylvania School of Medicine, 215 Stemmler Hall, Philadelphia, PA 19104; and Zentrum fur Biochemie and Molekulare Zellbiologie, Department of Biochemistry II, University of Gottingen, Humboldtalle 23, D-37073 Gottingen, Germany
Philip Thomas
Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom; Department of Neuroscience, University of Pennsylvania School of Medicine, 215 Stemmler Hall, Philadelphia, PA 19104; and Zentrum fur Biochemie and Molekulare Zellbiologie, Department of Biochemistry II, University of Gottingen, Humboldtalle 23, D-37073 Gottingen, Germany
Verena Tretter
Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom; Department of Neuroscience, University of Pennsylvania School of Medicine, 215 Stemmler Hall, Philadelphia, PA 19104; and Zentrum fur Biochemie and Molekulare Zellbiologie, Department of Biochemistry II, University of Gottingen, Humboldtalle 23, D-37073 Gottingen, Germany
Yuri D. Bogdanov
Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom; Department of Neuroscience, University of Pennsylvania School of Medicine, 215 Stemmler Hall, Philadelphia, PA 19104; and Zentrum fur Biochemie and Molekulare Zellbiologie, Department of Biochemistry II, University of Gottingen, Humboldtalle 23, D-37073 Gottingen, Germany
Volker Haucke
Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom; Department of Neuroscience, University of Pennsylvania School of Medicine, 215 Stemmler Hall, Philadelphia, PA 19104; and Zentrum fur Biochemie and Molekulare Zellbiologie, Department of Biochemistry II, University of Gottingen, Humboldtalle 23, D-37073 Gottingen, Germany
Trevor G. Smart
Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom; Department of Neuroscience, University of Pennsylvania School of Medicine, 215 Stemmler Hall, Philadelphia, PA 19104; and Zentrum fur Biochemie and Molekulare Zellbiologie, Department of Biochemistry II, University of Gottingen, Humboldtalle 23, D-37073 Gottingen, Germany
Stephen J. Moss§
Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom; Department of Neuroscience, University of Pennsylvania School of Medicine, 215 Stemmler Hall, Philadelphia, PA 19104; and Zentrum fur Biochemie and Molekulare Zellbiologie, Department of Biochemistry II, University of Gottingen, Humboldtalle 23, D-37073 Gottingen, Germany

Notes

§
To whom correspondence should be addressed. E-mail: [email protected].
Edited by Pietro V. De Camilli, Yale University School of Medicine, New Haven, CT, and approved July 7, 2004

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    Huntingtin-associated protein 1 regulates inhibitory synaptic transmission by modulating γ-aminobutyric acid type A receptor membrane trafficking
    Proceedings of the National Academy of Sciences
    • Vol. 101
    • No. 34
    • pp. 12399-12777

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