Calpain-Mediated mGluR1α Truncation: A Key Step in Excitotoxicity

Wei Xu, Tak Pan Wong, Nadege Chery, Tara Gaertner, Yu Tian Wang, Michel Baudry

Research output: Contribution to journalArticle

123 Citations (Scopus)

Abstract

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 mGluR1α at Ser936. The truncated mGluR1α maintains its ability to increase cytosolic calcium while it no longer activates the neuroprotective PI3K-Akt signaling pathways. Full-length and truncated forms of mGluR1α play distinct roles in excitotoxic neuronal degeneration in cultured neurons. A fusion peptide derived from the calpain cleavage site of mGluR1α efficiently blocks NMDA-induced truncation of mGluR1α 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 mGluR1α and indicate the existence of a positive feedback regulation in excitotoxicity involving calpain and mGluR1α.

Original languageEnglish (US)
Pages (from-to)399-412
Number of pages14
JournalNeuron
Volume53
Issue number3
DOIs
StatePublished - Feb 1 2007

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Calpain
N-Methylaspartate
Ionotropic Glutamate Receptors
Metabotropic Glutamate Receptors
metabotropic glutamate receptor type 1
Glutamate Receptors
N-Methyl-D-Aspartate Receptors
Phosphatidylinositol 3-Kinases
Neurodegenerative Diseases
Ischemia
Calcium
Neurons
Peptides

Keywords

  • cellbio
  • molneuro
  • signaling

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Xu, W., Wong, T. P., Chery, N., Gaertner, T., Wang, Y. T., & Baudry, M. (2007). Calpain-Mediated mGluR1α Truncation: A Key Step in Excitotoxicity. Neuron, 53(3), 399-412. https://doi.org/10.1016/j.neuron.2006.12.020

Calpain-Mediated mGluR1α Truncation : A Key Step in Excitotoxicity. / Xu, Wei; Wong, Tak Pan; Chery, Nadege; Gaertner, Tara; Wang, Yu Tian; Baudry, Michel.

In: Neuron, Vol. 53, No. 3, 01.02.2007, p. 399-412.

Research output: Contribution to journalArticle

Xu, W, Wong, TP, Chery, N, Gaertner, T, Wang, YT & Baudry, M 2007, 'Calpain-Mediated mGluR1α Truncation: A Key Step in Excitotoxicity', Neuron, vol. 53, no. 3, pp. 399-412. https://doi.org/10.1016/j.neuron.2006.12.020
Xu W, Wong TP, Chery N, Gaertner T, Wang YT, Baudry M. Calpain-Mediated mGluR1α Truncation: A Key Step in Excitotoxicity. Neuron. 2007 Feb 1;53(3):399-412. https://doi.org/10.1016/j.neuron.2006.12.020
Xu, Wei ; Wong, Tak Pan ; Chery, Nadege ; Gaertner, Tara ; Wang, Yu Tian ; Baudry, Michel. / Calpain-Mediated mGluR1α Truncation : A Key Step in Excitotoxicity. In: Neuron. 2007 ; Vol. 53, No. 3. pp. 399-412.
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