Fyn-mediated phosphorylation of NR2B Tyr-1336 controls calpain-mediated NR2B cleavage in neurons and heterologous systems

Hai Yan Wu, Fu Chun Hsu, Amy J. Gleichman, Isabelle Baconguis, Douglas A. Coulter, David R. Lynch

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Cleavage of the intracellular carboxyl terminus of the N-methyl-D-aspartate (NMDA) receptor 2 subunit (NR2) by calpain regulates NMDA receptor function and localization. Here, we show that Fyn-mediated phosphorylation of NR2B controls calpain-mediated NR2B cleavage. In cultured neurons, calpain-mediated NR2B cleavage is significantly attenuated by blocking NR2B phosphorylation of Tyr-1336, but not Tyr-1472, via inhibition of Src family kinase activity or decreasing Fyn levels by small interfering RNA. In HEK cells, mutation of Tyr-1336 eliminates the potentiating effect of Fyn on calpain-mediated NR2B cleavage. The potentiation of NR2B cleavage by Fyn is limited to cell surface receptors and is associated with calpain translocation to plasma membranes during NMDA receptor activation. Finally, reducing full-length NR2B by calpain does not decrease extrasynaptic NMDA receptor function, and truncated NR1/2B receptors similar to those generated by calpain have electrophysiological properties matching those of wild-type receptors. Thus, the Fyn-controlled regulation of NMDA receptor cleavage by calpain may play critical roles in controlling NMDA receptor properties during synaptic plasticity and excitotoxicity.

Original languageEnglish (US)
Pages (from-to)20075-20087
Number of pages13
JournalJournal of Biological Chemistry
Volume282
Issue number28
DOIs
StatePublished - Jul 13 2007
Externally publishedYes

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Phosphorylation
Calpain
Neurons
N-Methyl-D-Aspartate Receptors
Neuronal Plasticity
src-Family Kinases
Cell Surface Receptors
Cell membranes
Small Interfering RNA
Plasticity
Chemical activation
Cell Membrane
Mutation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Fyn-mediated phosphorylation of NR2B Tyr-1336 controls calpain-mediated NR2B cleavage in neurons and heterologous systems. / Wu, Hai Yan; Hsu, Fu Chun; Gleichman, Amy J.; Baconguis, Isabelle; Coulter, Douglas A.; Lynch, David R.

In: Journal of Biological Chemistry, Vol. 282, No. 28, 13.07.2007, p. 20075-20087.

Research output: Contribution to journalArticle

Wu, Hai Yan ; Hsu, Fu Chun ; Gleichman, Amy J. ; Baconguis, Isabelle ; Coulter, Douglas A. ; Lynch, David R. / Fyn-mediated phosphorylation of NR2B Tyr-1336 controls calpain-mediated NR2B cleavage in neurons and heterologous systems. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 28. pp. 20075-20087.
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