Glutamate induces neurotrophic factor production from microglia via protein kinase C pathway.
Microglia are intrinsic immune cells in the central nervous system and play key roles in the pathogenesis of various central nervous system disorders. Microglia have been shown to attack damaged neurons by secreting a variety of neurotoxic factors including inflammatory cytokines, reactive oxygen species and glutamate. On the other hand, they can produce neurotrophic factors (NTFs) which support neuronal survival and growth. However, the precise mechanism that regulates microglial NTF production is not fully understood, and the relation between glutamate and NTFs remains unclear. In the present study, we show that glutamate significantly induces microglial NTF production by the activation of N-methyl-d-aspartate (NMDA) receptors, group III metabotropic glutamate receptors, and glutamate transporters. Activation of NMDA receptors and group III metabotropic glutamate receptors induces intracellular Ca(2+) release from the endoplasmic reticulum. Further, stimulation of glutamate transporters leads to influx of extracellular Ca(2+) in a Na(+)-dependent manner. This intracellular Ca(2+) elevation activates the protein kinase C pathway which induces microglial NTF expression and production. These results suggest that microglia play a neuroprotective role during the excitotoxic state in neurodegenerative diseases.
Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
Jianfeng
J
Liang
Hideyuki
H
Takeuchi
Shijie
S
Jin
Mariko
M
Noda
Hua
H
Li
Yukiko
Y
Doi
Jun
J
Kawanokuchi
Yoshifumi
Y
Sonobe
Tetsuya
T
Mizuno
Akio
A
Suzumura
D027322:Amino Acid Transport System X-AG / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004660:Encephalitis / Q000378:metabolism* / Q000503:physiopathology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D009414:Nerve Growth Factors / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D027322:Amino Acid Transport System X-AG; D009414:Nerve Growth Factors; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C102718:metabotropic glutamate receptor 3; D018698:Glutamic Acid; D011493:Protein Kinase C; D002118:Calcium