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The Journal of Neuroscience, October 15, 2008, 28(42):10696-10710; doi:10.1523/JNEUROSCI.1207-08.2008

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Cellular/Molecular
Specific Targeting of Pro-Death NMDA Receptor Signals with Differing Reliance on the NR2B PDZ Ligand

Francesc X. Soriano,^1,2 * Marc-Andre Martel,^1,2 * Sofia Papadia,^1,2 Anne Vaslin,³ Paul Baxter,^1,2 Colin Rickman,¹ Joan Forder,⁴ Michael Tymianski,⁴ Rory Duncan,¹ Michelle Aarts,⁵ Peter G. H. Clarke,³ David J. A. Wyllie,^1,2 and Giles E. Hardingham^1,2

Centres for ¹Integrative Physiology and ²Neuroscience Research, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, ³Département de Biologie Cellulaire et de Morphologie, Université de Lausanne, CH-1015 Lausanne, Switzerland, ⁴Department of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada M5T 2S8, and ⁵Centre for the Neurobiology of Stress, University of Toronto at Scarborough, Scarborough, Ontario, Canada M1C 1A4

Correspondence should be addressed to Giles E. Hardingham at the above address. Email: giles.hardingham{at}ed.ac.uk

NMDA receptors (NMDARs) mediate ischemic brain damage, for which interactions between the C termini of NR2 subunits and PDZ domain proteins within the NMDAR signaling complex (NSC) are emerging therapeutic targets. However, expression of NMDARs in a non-neuronal context, lacking many NSC components, can still induce cell death. Moreover, it is unclear whether targeting the NSC will impair NMDAR-dependent prosurvival and plasticity signaling. We show that the NMDAR can promote death signaling independently of the NR2 PDZ ligand, when expressed in non-neuronal cells lacking PSD-95 and neuronal nitric oxide synthase (nNOS), key PDZ proteins that mediate neuronal NMDAR excitotoxicity. However, in a non-neuronal context, the NMDAR promotes cell death solely via c-Jun N-terminal protein kinase (JNK), whereas NMDAR-dependent cortical neuronal death is promoted by both JNK and p38. NMDAR-dependent pro-death signaling via p38 relies on neuronal context, although death signaling by JNK, triggered by mitochondrial reactive oxygen species production, does not. NMDAR-dependent p38 activation in neurons is triggered by submembranous Ca²⁺, and is disrupted by NOS inhibitors and also a peptide mimicking the NR2B PDZ ligand (TAT-NR2B9c). TAT-NR2B9c reduced excitotoxic neuronal death and p38-mediated ischemic damage, without impairing an NMDAR-dependent plasticity model or prosurvival signaling to CREB or Akt. TAT-NR2B9c did not inhibit JNK activation, and synergized with JNK inhibitors to ameliorate severe excitotoxic neuronal loss in vitro and ischemic cortical damage in vivo. Thus, NMDAR-activated signals comprise pro-death pathways with differing requirements for PDZ protein interactions. These signals are amenable to selective inhibition, while sparing synaptic plasticity and prosurvival signaling.

Key words: NMDA receptor; neuronal death; PDZ domains; stroke; calcium; mitochondria; neuroprotection; nitric oxide; protein kinase; signal transduction

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Received Aug. 26, 2008; accepted Aug. 28, 2008.

Correspondence should be addressed to Giles E. Hardingham at the above address. Email: giles.hardingham{at}ed.ac.uk

This article has been cited by other articles:

				R. I. Stanika, N. B. Pivovarova, C. A. Brantner, C. A. Watts, C. A. Winters, and S. B. Andrews Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity PNAS, June 16, 2009; 106(24): 9854 - 9859. [Abstract] [Full Text] [PDF]

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