Calpain-mediated mGluR1alpha truncation: a key step in excitotoxicity.
Excitotoxicity mediated by glutamate receptors plays crucial roles in ischemia and other neurodegenerative diseases. Whereas overactivation of ionotropic glutamate receptors is neurotoxic, the role of metabotropic glutamate receptors (mGluRs), and especially mGluR1, remains equivocal. Here we report that activation of NMDA receptors results in calpain-mediated truncation of the C-terminal domain of mGluR1alpha at Ser(936). The truncated mGluR1alpha maintains its ability to increase cytosolic calcium while it no longer activates the neuroprotective PI(3)K-Akt signaling pathways. Full-length and truncated forms of mGluR1alpha play distinct roles in excitotoxic neuronal degeneration in cultured neurons. A fusion peptide derived from the calpain cleavage site of mGluR1alpha efficiently blocks NMDA-induced truncation of mGluR1alpha in primary neuronal cultures and exhibits neuroprotection against excitotoxicity both in vitro and in vivo. These findings shed light on the relationship between NMDA and mGluR1alpha and indicate the existence of a positive feedback regulation in excitotoxicity involving calpain and mGluR1alpha.
Xu
Wei
W
Neuroscience Program, University of Southern California, Los Angeles, CA 90089-2520, USA.
Wong
Tak Pan
TP
Chery
Nadege
N
Gaertner
Tara
T
Wang
Yu Tian
YT
Baudry
Michel
M
D000818:Animals; D002154:Calpain / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018846:Excitatory Amino Acids / Q000633:toxicity*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000633:toxicity; D009474:Neurons / Q000502:physiology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D016622:Silver Staining; D014162:Transfection
D018690:Excitatory Amino Acid Agonists; D018846:Excitatory Amino Acids; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C104077:metabotropic glutamate receptor type 1; D002154:Calpain; D007608:Kainic Acid