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The Journal of Neuroscience, February 28, 2007, 27(9):2298-2308; doi:10.1523/JNEUROSCI.5175-06.2007

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Neurobiology of Disease
NMDA Receptor Function and NMDA Receptor-Dependent Phosphorylation of Huntingtin Is Altered by the Endocytic Protein HIP1

Martina Metzler,¹ Lu Gan,¹ Tak Pan Wong,² Lidong Liu,² Jeffrey Helm,¹ Lili Liu,¹ John Georgiou,³ Yushan Wang,² Nagat Bissada,¹ Kevin Cheng,¹ John C. Roder,³ Yu Tian Wang,² and Michael R. Hayden¹

¹Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4, ²Department of Medicine and The Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3, and ³Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5

Correspondence should be addressed to Dr. Michael R. Hayden, Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, 980 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4. Email: mrh{at}cmmt.ubc.ca

Huntingtin-interacting protein 1 (HIP1) is an endocytic adaptor protein that plays a role in clathrin-mediated endocytosis and the ligand-induced internalization of AMPA receptors (AMPARs) (Metzler et al., 2003). In the present study, we investigated the role of HIP1 in NMDA receptor (NMDAR) function by analyzing NMDA-dependent transport and NMDA-induced excitotoxicity in neurons from HIP1^–/– mice. HIP1 colocalizes with NMDARs in hippocampal and cortical neurons and affinity purifies with NMDARs by GST (glutathione S-transferase) pull down and coimmunoprecipitation. A profound decrease in NMDA-induced AMPAR internalization of 75% occurs in neurons from HIP1^–/– mice compared with wild type, using a quantitative single-cell-based internalization assay. This defect in NMDA-dependent removal of surface AMPARs is in agreement with the observed defect in long-term depression induction in hippocampal brain slices of HIP1^–/– mice and supports a role of HIP1 in AMPAR internalization in vivo. HIP1^–/– neurons are partially protected from NMDA-induced excitotoxicity as assessed by LDH (lactate dehydrogenase) release, TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling) and caspase-3 activation assays, which points to a role of HIP1 in NMDA-induced cell death. Interestingly, phosphorylation of Akt and its substrate huntingtin (htt) decreases during NMDA-induced excitotoxicity by 48 and 31%, respectively. This decrease is significantly modulated by HIP1, resulting in 94 and 48% changes in P-Akt and P-htt levels in HIP1^–/– neurons, respectively. In summary, we have shown that HIP1 influences important NMDAR functions and that both HIP1 and htt participate in NMDA-induced cell death. These findings may provide novel insights into the cellular mechanisms underlying enhanced NMDA-induced excitotoxicity in Huntington's disease.

Key words: Huntington's disease; neurodegeneration; glutamate receptors; excitotoxicity; transport; synapse

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Received Aug. 22, 2006; revised Jan. 12, 2007; accepted Jan. 15, 2007.

Correspondence should be addressed to Dr. Michael R. Hayden, Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, 980 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4. Email: mrh{at}cmmt.ubc.ca

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				J. A. Parker, M. Metzler, J. Georgiou, M. Mage, J. C. Roder, A. M. Rose, M. R. Hayden, and C. Neri Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and Protects Caenorhabditis elegans Neurons against Mutant Polyglutamine Toxicity J. Neurosci., October 10, 2007; 27(41): 11056 - 11064. [Abstract] [Full Text] [PDF]

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