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Molecular Pharmacology

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Research ArticleArticle

N-Methyl-d-aspartate Attenuates CXCR2-Mediated Neuroprotection through Enhancing the Receptor Phosphorylation and Blocking the Receptor Recycling

Qingwei Luo, Yun Ding, Kurt Watson, Jingwu Zhang and Guo-Huang Fan
Molecular Pharmacology August 2005, 68 (2) 528-537; DOI: https://doi.org/10.1124/mol.105.011197
Qingwei Luo
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Yun Ding
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Kurt Watson
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Jingwu Zhang
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Guo-Huang Fan
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Abstract

Abnormal extracellular accumulations of β-amyloid, a major component of the senile plaques, and of the excitatory amino acid glutamate are both believed to be associated with degeneration of nerve cells in the central nervous system of patients with Alzheimer's disease. The chemokine receptor CXCR2 has been shown to play a role in protecting neurons against β-amyloid–induced injury in vitro, but it remains unclear whether CXCR2-mediated neuroprotection is affected by glutamate. We demonstrated that pretreatment of hippocampal neurons with a sublethal concentration of N-methyl-d-aspartate (NMDA) attenuated the macrophage inflammatory protein 2 (MIP2)-induced protection against β-amyloid–induced neuronal death. The NMDA induced inhibition was blocked by (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), a noncompetitive NMDA receptor antagonist, indicating the involvement of NMDA receptors in this process. A sublethal dose of NMDA pretreatment induced CXCR2 phosphorylation, although to a lesser extent than the receptor phosphorylation induced by MIP2, and differential serine residues were involved in NMDA- and MIP2-induced CXCR2 phosphorylation. Moreover, NMDA treatment reduced the CXCR2-mediated Ca2+ mobilization, suggesting that NMDA induces cross-desensitization of CXCR2. CXCR2 underwent dephosphorylation after removal of the extracellular ligand, but the dephosphorylation rate was significantly reduced in the cells pretreated with NMDA. Treatment of the neuronal cells with NMDA retarded the recycling of CXCR2. In view of the critical role of receptor phosphorylation and recycling in the functional responsiveness of the chemokine receptor, these observations indicate a novel pathway through which glutamate may interfere with the neuroprotective function of chemokines.

  • Received January 19, 2005.
  • Accepted May 24, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 68 (2)
Molecular Pharmacology
Vol. 68, Issue 2
1 Aug 2005
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Research ArticleArticle

N-Methyl-d-aspartate Attenuates CXCR2-Mediated Neuroprotection through Enhancing the Receptor Phosphorylation and Blocking the Receptor Recycling

Qingwei Luo, Yun Ding, Kurt Watson, Jingwu Zhang and Guo-Huang Fan
Molecular Pharmacology August 1, 2005, 68 (2) 528-537; DOI: https://doi.org/10.1124/mol.105.011197

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Research ArticleArticle

N-Methyl-d-aspartate Attenuates CXCR2-Mediated Neuroprotection through Enhancing the Receptor Phosphorylation and Blocking the Receptor Recycling

Qingwei Luo, Yun Ding, Kurt Watson, Jingwu Zhang and Guo-Huang Fan
Molecular Pharmacology August 1, 2005, 68 (2) 528-537; DOI: https://doi.org/10.1124/mol.105.011197
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