The removal of extracellular calcium: a novel mechanism underlying the recruitment of N-methyl-D-aspartate (NMDA) receptors in neurotoxicity.
The involvement of NMDA-type glutamate receptor in neuronal injury established in experimental stroke and neurotrauma models has been recently challenged by failures in treatment of stroke/neurotrauma patients with NMDA receptor antagonists. NMDA receptor activity is known to be essential for mediating a multitude of physiological functions. However, how NMDA receptors are recruited to cause neuronal injury remains unclear. Here we report that the time period during which initial NMDA receptor up-regulation occurs is critical for the recruitment of NMDA receptors causing neuronal injury during extracellular calcium (Ca2+) reperfusion in cultured hippocampal neurons, and represents the key period for neuronal protection by NMDA receptor antagonists. Furthermore, we identified that via intracellular sodium (Na+), extracellular Ca2+ depletion induces the up-regulation of NMDA receptor gating. Taken together, our study provides direct experimental evidence suggesting that determination of when and how NMDA receptors are recruited to cause neurotoxicity is essential for guiding treatment via antagonism of NMDA receptor functions.
Xin
Wen-Kuan
WK
Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
Zhao
Xiao-Han
XH
Xu
Jindong
J
Lei
Gang
G
Kwan
Chun L
CL
Zhu
Kang-Min
KM
Cho
Jae-Sung
JS
Duff
Missy
M
Ellen
Richard P
RP
McCulloch
Christopher A G
CA
Yu
Xian-Min
XM
D000818:Animals; D002118:Calcium / Q000008:administration & dosage* / Q000172:deficiency*; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*
D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D002118:Calcium