N-methyl-D-aspartate attenuates CXCR2-mediated neuroprotection through enhancing the receptor phosphorylation and blocking the receptor recycling.
Abnormal extracellular accumulations of beta-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 beta-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 beta-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 Ca(2+) 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.
Luo
Qingwei
Q
Department of Pharmacology, Meharry Medical College, 1005 Dr. D. B Todd Jr Blvd, Nashville, TN 37208, USA.
Ding
Yun
Y
Watson
Kurt
K
Zhang
Jingwu
J
Fan
Guo-Huang
GH
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*
D023063:Receptors, Interleukin-8B; D016202:N-Methylaspartate