QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, September 12, 2007, 27(37):9901-9915; doi:10.1523/JNEUROSCI.1464-07.2007

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (26) Citing Articles via Google Scholar Google Scholar Articles by Cui, H. Articles by Tymianski, M. Search for Related Content PubMed PubMed Citation Articles by Cui, H. Articles by Tymianski, M.

 Previous Article  |  Next Article 

Neurobiology of Disease
PDZ Protein Interactions Underlying NMDA Receptor-Mediated Excitotoxicity and Neuroprotection by PSD-95 Inhibitors

Hong Cui,³ Amy Hayashi,¹ Hong-Shuo Sun,¹ Michael P. Belmares,² Carolyn Cobey,² Thuymy Phan,² Johannes Schweizer,² Michael W. Salter,^3,5 Yu Tian Wang,⁶ R. Andrew Tasker,⁴ David Garman,² Joshua Rabinowitz,⁷ Peter S. Lu,² and Michael Tymianski^1,3

¹Toronto Western Hospital Research Institute, Toronto, Ontario, Canada M5T 2S8, ²Arbor Vita Corporation, Sunnyvale, California 94085, ³NoNO Inc., Toronto, Ontario, Canada M8X 1R5, ⁴Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada C1A 4P3, ⁵Programme in Brain and Behaviour, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8, ⁶Brain Research Center and Department of Medicine, Vancouver Hospital and Health Sciences Center, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3, and ⁷Lewis Sigler Institute for Integrative Genomics and Departments of Molecular Biology and Chemistry, Princeton University, Princeton, New Jersey 08544

Correspondence should be addressed to Dr. Michael Tymianski, Toronto Western Hospital, WW 4-435, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. Email: mike.tymianski{at}uhn.on.ca

In neuronal synapses, PDZ domains [postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1] of PSD-95 proteins interact with C termini of NMDA receptor [NMDAR (NR)] subunits, linking them to downstream neurotoxic signaling molecules. Perturbing NMDAR/PSD-95 interactions with a Tat peptide comprising the nine C-terminal residues of the NR2B subunit (Tat-NR2B9c) reduces neurons' vulnerability to excitotoxicity and ischemia. However, NR subunit C termini may bind many of >240 cellular PDZs, any of which could mediate neurotoxic signaling independently of PSD-95. Here, we performed a proteomic and biochemical analysis of the interactions of all known human PDZs with synaptic signaling proteins including NR1, NR2A–NR2D, and neuronal nitric oxide synthase (nNOS). Tat-NR2B9c, whose interactions define PDZs involved in neurotoxic signaling, was also used. NR2A–NR2D subunits and Tat-NR2B9c had similar, highly specific, PDZ protein interactions, of which the strongest were with the PSD-95 family members (PSD-95, PSD-93, SAP97, and SAP102) and Tax interaction protein 1 (TIP1). The PSD-95 PDZ2 domain bound NR2A–NR2C subunits most strongly (EC₅₀, 1 µM), and fusing the NR2B C terminus to Tat enhanced its affinity for PSD-95 PDZ2 by >100-fold (EC₅₀, 7 nM). IC₅₀ values for Tat-NR2B9c inhibiting NR2A–NR2C/PSD-95 interactions (1–10 µM) and nNOS/PSD-95 interactions (200 nM) confirmed the feasibility of such inhibition. To determine which of the PDZ interactions of Tat-NR2B9c mediate neuroprotection, one of PSD-95, PSD-93, SAP97, SAP102, TIP1, or nNOS expression was inhibited in cortical neurons exposed to NMDA toxicity. Only neurons lacking PSD-95 or nNOS but not PSD-93, SAP97, SAP102, or TIP1 exhibited reduced excitotoxic vulnerability. Thus, despite the ubiquitousness of PDZ domain-containing proteins, PSD-95 and nNOS above any other PDZ proteins are keys in effecting NMDAR-dependent excitotoxicity. Consequently, PSD-95 inhibition may constitute a highly specific strategy for treating excitotoxic disorders.

Key words: PDZ domains; PSD-95; NMDA receptors; excitotoxicity; RNA interference; nitric oxide synthase

---

Received April 1, 2007; revised June 20, 2007; accepted July 22, 2007.

Correspondence should be addressed to Dr. Michael Tymianski, Toronto Western Hospital, WW 4-435, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. Email: mike.tymianski{at}uhn.on.ca

This article has been cited by other articles:

				A. Chaudhury, X.-D. He, and R. K. Goyal Role of PSD95 in membrane association and catalytic activity of nNOS{alpha} in nitrergic varicosities in mice gut Am J Physiol Gastrointest Liver Physiol, October 1, 2009; 297(4): G806 - G813. [Abstract] [Full Text] [PDF]

				C. Lopez-Menendez, S. Gascon, M. Sobrado, O. G. Vidaurre, A. M. Higuero, A. Rodriguez-Pena, T. Iglesias, and M. Diaz-Guerra Kidins220/ARMS downregulation by excitotoxic activation of NMDARs reveals its involvement in neuronal survival and death pathways J. Cell Sci., October 1, 2009; 122(19): 3554 - 3565. [Abstract] [Full Text] [PDF]

				J. Fan, C. M. Cowan, L. Y. J. Zhang, M. R. Hayden, and L. A. Raymond Interaction of Postsynaptic Density Protein-95 with NMDA Receptors Influences Excitotoxicity in the Yeast Artificial Chromosome Mouse Model of Huntington's Disease J. Neurosci., September 2, 2009; 29(35): 10928 - 10938. [Abstract] [Full Text] [PDF]

				S.-H. Yeh, J.-J. Hung, P.-W. Gean, and W.-C. Chang Hypoxia-Inducible Factor-1{alpha} Protects Cultured Cortical Neurons from Lipopolysaccharide-Induced Cell Death via Regulation of NR1 Expression J. Neurosci., December 24, 2008; 28(52): 14259 - 14270. [Abstract] [Full Text] [PDF]

				F. X. Soriano, M.-A. Martel, S. Papadia, A. Vaslin, P. Baxter, C. Rickman, J. Forder, M. Tymianski, R. Duncan, M. Aarts, et al. Specific Targeting of Pro-Death NMDA Receptor Signals with Differing Reliance on the NR2B PDZ Ligand J. Neurosci., October 15, 2008; 28(42): 10696 - 10710. [Abstract] [Full Text] [PDF]

				C. E. Flores, X. Li, M. V. L. Bennett, J. I. Nagy, and A. E. Pereda Interaction between connexin35 and zonula occludens-1 and its potential role in the regulation of electrical synapses PNAS, August 26, 2008; 105(34): 12545 - 12550. [Abstract] [Full Text] [PDF]

				E. Y. Yuen, Y. Ren, and Z. Yan Postsynaptic Density-95 (PSD-95) and Calcineurin Control the Sensitivity of N-Methyl-D-aspartate Receptors to Calpain Cleavage in Cortical Neurons Mol. Pharmacol., August 1, 2008; 74(2): 360 - 370. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help