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The Journal of Neuroscience, July 22, 2009, 29(29):9330-9343; doi:10.1523/JNEUROSCI.2212-09.2009

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Development/Plasticity/Repair
Extrasynaptic NMDA Receptors Couple Preferentially to Excitotoxicity via Calpain-Mediated Cleavage of STEP

Jian Xu,¹ Pradeep Kurup,¹ Yongfang Zhang,¹ Susan M. Goebel-Goody,¹ Peter H. Wu,² Ammar H. Hawasli,³ Matthew L. Baum,¹ James A. Bibb,³ and Paul J. Lombroso¹

¹The Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, ²Department of Psychiatry, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, and ³Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Correspondence should be addressed to Dr. Paul J. Lombroso, Child Study Center, SHM I-270, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520. Email: paul.lombroso{at}yale.edu

NMDA receptor (NMDAR)-mediated excitotoxicity plays an important role in several CNS disorders, including epilepsy, stroke, and ischemia. Here we demonstrate the involvement of striatal-enriched protein tyrosine phosphatase (STEP) in this critical process. STEP₆₁ is an alternatively spliced member of the family that is present in postsynaptic terminals. In an apparent paradox, STEP₆₁ regulates extracellular signal-regulated kinase 1/2 (ERK1/2) and p38, two proteins with opposing functions; activated p38 promotes cell death, whereas activated ERK1/2 promotes cell survival. We found that synaptic stimulation of NMDARs promoted STEP₆₁ ubiquitination and degradation, concomitant with ERK1/2 activation. In contrast, extrasynaptic stimulation of NMDARs invoked calpain-mediated proteolysis of STEP₆₁, producing the truncated cleavage product STEP₃₃ and activation of p38. The calpain cleavage site on STEP was mapped to the kinase interacting motif, a domain required for substrate binding. As a result, STEP₃₃ neither interacts with nor dephosphorylates STEP substrates. A synthetic peptide spanning the calpain cleavage site efficiently reduced STEP₆₁ degradation and attenuated p38 activation and cell death in slice models. Furthermore, this peptide was neuroprotective when neurons were subjected to excitotoxicity or cortical slices were exposed to ischemic conditions. These findings suggest a novel mechanism by which differential NMDAR stimulation regulates STEP₆₁ to promote either ERK1/2 or p38 activation and identifies calpain cleavage of STEP₆₁ as a valid target for the development of neuroprotective therapy.

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Received May 11, 2009; revised June 8, 2009; accepted June 15, 2009.

Correspondence should be addressed to Dr. Paul J. Lombroso, Child Study Center, SHM I-270, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520. Email: paul.lombroso{at}yale.edu

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