Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP

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

Research output: Contribution to journalArticle

173 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)9330-9343
Number of pages14
JournalJournal of Neuroscience
Volume29
Issue number29
DOIs
StatePublished - Jul 22 2009

Fingerprint

Corpus Striatum
Protein Tyrosine Phosphatases
Calpain
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
N-Methyl-D-Aspartate Receptors
Cell Death
Peptides
Ubiquitination
Proteolysis
Epilepsy
Cell Survival
Phosphotransferases
Ischemia
Stroke
Neurons
Proteins
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Xu, J., Kurup, P., Zhang, Y., Goebel-Goody, S. M., Wu, P. H., Hawasli, A. H., ... Lombroso, P. J. (2009). Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. Journal of Neuroscience, 29(29), 9330-9343. https://doi.org/10.1523/JNEUROSCI.2212-09.2009

Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. / Xu, Jian; Kurup, Pradeep; Zhang, Yongfang; Goebel-Goody, Susan M.; Wu, Peter H.; Hawasli, Ammar H.; Baum, Matthew L.; Bibb, James A.; Lombroso, Paul J.

In: Journal of Neuroscience, Vol. 29, No. 29, 22.07.2009, p. 9330-9343.

Research output: Contribution to journalArticle

Xu, J, Kurup, P, Zhang, Y, Goebel-Goody, SM, Wu, PH, Hawasli, AH, Baum, ML, Bibb, JA & Lombroso, PJ 2009, 'Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP', Journal of Neuroscience, vol. 29, no. 29, pp. 9330-9343. https://doi.org/10.1523/JNEUROSCI.2212-09.2009
Xu, Jian ; Kurup, Pradeep ; Zhang, Yongfang ; Goebel-Goody, Susan M. ; Wu, Peter H. ; Hawasli, Ammar H. ; Baum, Matthew L. ; Bibb, James A. ; Lombroso, Paul J. / Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. In: Journal of Neuroscience. 2009 ; Vol. 29, No. 29. pp. 9330-9343.
@article{a0cf4adb19874947bb30e8f79f3db89a,
title = "Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP",
abstract = "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.",
author = "Jian Xu and Pradeep Kurup and Yongfang Zhang and Goebel-Goody, {Susan M.} and Wu, {Peter H.} and Hawasli, {Ammar H.} and Baum, {Matthew L.} and Bibb, {James A.} and Lombroso, {Paul J.}",
year = "2009",
month = "7",
day = "22",
doi = "10.1523/JNEUROSCI.2212-09.2009",
language = "English (US)",
volume = "29",
pages = "9330--9343",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "29",

}

TY - JOUR

T1 - Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP

AU - Xu, Jian

AU - Kurup, Pradeep

AU - Zhang, Yongfang

AU - Goebel-Goody, Susan M.

AU - Wu, Peter H.

AU - Hawasli, Ammar H.

AU - Baum, Matthew L.

AU - Bibb, James A.

AU - Lombroso, Paul J.

PY - 2009/7/22

Y1 - 2009/7/22

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=67651172947&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67651172947&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.2212-09.2009

DO - 10.1523/JNEUROSCI.2212-09.2009

M3 - Article

C2 - 19625523

AN - SCOPUS:67651172947

VL - 29

SP - 9330

EP - 9343

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 29

ER -