alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptor (AMPAR) endocytosis is essential for N-methyl-D-aspartate-induced neuronal apoptosis.
Excessive activation of the N-methyl-d-aspartate subtype glutamate receptor (NMDAR) is thought to be involved in mediating programmed cell death (apoptosis) in numerous central nervous diseases. However, the underlying mechanisms remain unknown. We report here that stimulation of NMDARs activates intracellular signaling cascades leading to apoptosis and facilitates clathrin-dependent endocytosis of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors (AMPARs). Both broad spectrum inhibitors of clathrin-dependent endocytotic processes and a specific inhibitor of AMPAR endocytosis selectively inhibit NMDA-induced apoptosis without affecting apoptosis produced by staurosporine. These results demonstrate that clathrin-dependent endocytosis of AMPARs is an essential step in NMDAR-mediated neuronal apoptosis. Our study not only identifies a previously unsuspected step in NMDA-induced apoptosis but also demonstrates that AMPAR endocytosis, in addition to attenuating synaptic strength as previously demonstrated in models of synaptic plasticity, may play a critical role in mediating other important intracellular pathways.
Brain Research Centre and Department of Medicine, Vancouver Hospital & Health Sciences Centre, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada. ytwang@interchange.ubc.ca
Yushan
Y
Wang
William
W
Ju
Lidong
L
Liu
Sami
S
Fam
Sandra
S
D'Souza
Changiz
C
Taghibiglou
Michael
M
Salter
Yu Tian
YT
Wang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D022163:Clathrin-Coated Vesicles / Q000502:physiology; D004705:Endocytosis / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D015398:Signal Transduction
D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C492973:alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptor, human; D016202:N-Methylaspartate