Calpain-mediated degradation of myocyte enhancer factor 2D contributes to excitotoxicity by activation of extrasynaptic N-methyl-D-aspartate receptors.
Synaptic and extrasynaptic NMDA receptors (NMDARs) appear to play opposite roles in neuronal survival and death. Here we report the new findings on the dysregulation of survival factor, myocyte enhancer factor 2D (MEF2D), by extrasynaptic NMDARs. Excitotoxicity led to the NMDAR-dependent degradation of MEF2D protein and inhibition of its transactivation activity in mature cortical neurons. The activation of extrasynaptic NMDARs alone was sufficient for degradation of MEF2D. Calpain directly cleaved MEF2D in vitro and blocking this protease activity greatly attenuated NMDAR signaled degradation of MEF2D in neurons. Consistently, inhibition of calpain protected cortical neurons from NMDA-induced excitotoxicity. Furthermore, knockdown of MEF2D sensitized neurons to NMDA-induced excitotoxicity, which was not protected by calpain inhibition. Collectively, these findings suggest that dysregulation of MEF2D by calpain may mediate excitotoxicity via an extrasynaptic NMDAR-dependent manner.
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Gengze
G
Wei
Yue
Y
Yin
Wenming
W
Li
Haruhiko
H
Bito
Hua
H
She
Zixu
Z
Mao
D000818:Animals; D002154:Calpain / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D064326:MEF2 Transcription Factors; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D059748:Proteolysis / Q000187:drug effects*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D064326:MEF2 Transcription Factors; C578045:MEF2D protein, rat; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; D016202:N-Methylaspartate; D002154:Calpain; D005947:Glucose