JPET xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Guttmann, R. P.
Right arrow Articles by Lynch, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Guttmann, R. P.
Right arrow Articles by Lynch, D. R.

Vol. 302, Issue 3, 1023-1030, September 2002

Proteolysis of the N-Methyl-D-Aspartate Receptor by Calpain in Situ

Rodney P. Guttmann, Set Sokol, Dana L. Baker, Kelly L. Simpkins, Yina Dong and David R. Lynch

Departments of Pharmacology (R.P.G.), Neurology (S.S., D.L.B., K.L.S., Y.D., D.R.L.), and Pediatrics (D.R.L.), University of Pennsylvania, School of Medicine, Children's Seashore House, Philadelphia, Pennsylvania

N-Methyl-D-aspartate (NMDA) receptors are calcium-permeable glutamate receptors that play putative roles in learning, memory, and excitotoxicity. NMDA receptor-mediated calcium entry can activate the calcium-dependent protease calpain, leading to substrate degradation. The major NMDA receptor 2 (NR2) subunits of the receptor are in vitro substrates for calpain at selected sites in the C-terminal region. In the present study, we assessed the ability of calpain-mediated proteolysis to modulate the NR1a/2A subtype in a heterologous expression system. Human embryonic kidney (HEK293t) cells, which endogenously express calpain, were cotransfected with NR1a/2A in addition to the calpain inhibitor calpastatin or empty vector as control. Receptor activation by glutamate and glycine as co-agonists led to calpain activation as measured by succinyl-L-leucyl-L-leucyl-L-valyl-L-tyrosyl-aminomethyl coumarin (Suc-LLVY-AMC). Calpain activation also resulted in the degradation of NR2A and decreased binding of 125I-MK-801 (125I-dizocilpine) to NR1a/2A receptors. No stable N-terminal fragment of the NMDA receptor was formed after calpain activation, suggesting calpain regulation of NMDA receptor levels in ways distinct from that previously observed with in vitro cleavage. NR2 subunit constructs lacking the final 420 amino acids were not degraded by calpain. Agonist-stimulated NR1a/2A-transfected cells also had decreased calcium uptake and produced lower changes in agonist-stimulated intracellular calcium compared with cells cotransfected with calpastatin. Calpastatin had no effect on either calcium uptake or intracellular calcium levels when the NR2A subunit lacked the final 420 amino acids. These studies demonstrate that NR2A is a substrate for calpain in situ and that this proteolytic event can modulate NMDA receptor levels.

0022-3565/02/3023-1023$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
E. Y. Yuen, Y. Ren, and Z. Yan
Postsynaptic Density-95 (PSD-95) and Calcineurin Control the Sensitivity of N-Methyl-D-aspartate Receptors to Calpain Cleavage in Cortical Neurons
Mol. Pharmacol., August 1, 2008; 74(2): 360 - 370.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H.-Y. Wu, F.-C. Hsu, A. J. Gleichman, I. Baconguis, D. A. Coulter, and D. R. Lynch
Fyn-mediated Phosphorylation of NR2B Tyr-1336 Controls Calpain-mediated NR2B Cleavage in Neurons and Heterologous Systems
J. Biol. Chem., July 13, 2007; 282(28): 20075 - 20087.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. Mercado, V. Broumand, K. Zandi-Nejad, A. H. Enck, and D. B. Mount
A C-terminal Domain in KCC2 Confers Constitutive K+-Cl- Cotransport
J. Biol. Chem., January 13, 2006; 281(2): 1016 - 1026.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H.-Y. Wu, E. Y. Yuen, Y.-F. Lu, M. Matsushita, H. Matsui, Z. Yan, and K. Tomizawa
Regulation of N-Methyl-D-aspartate Receptors by Calpain in Cortical Neurons
J. Biol. Chem., June 3, 2005; 280(22): 21588 - 21593.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. Tremper-Wells and M. L. Vallano
Nuclear Calpain Regulates Ca2+-dependent Signaling via Proteolysis of Nuclear Ca2+/Calmodulin-dependent Protein Kinase Type IV in Cultured Neurons
J. Biol. Chem., January 21, 2005; 280(3): 2165 - 2175.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
Y. N. Dong, E. A. Waxman, and D. R. Lynch
Interactions of Postsynaptic Density-95 and the NMDA Receptor 2 Subunit Control Calpain-Mediated Cleavage of the NMDA Receptor
J. Neurosci., December 8, 2004; 24(49): 11035 - 11045.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Gafni, E. Hermel, J. E. Young, C. L. Wellington, M. R. Hayden, and L. M. Ellerby
Inhibition of Calpain Cleavage of Huntingtin Reduces Toxicity: ACCUMULATION OF CALPAIN/CASPASE FRAGMENTS IN THE NUCLEUS
J. Biol. Chem., May 7, 2004; 279(19): 20211 - 20220.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
K. L. Simpkins, R. P. Guttmann, Y. Dong, Z. Chen, S. Sokol, R. W. Neumar, and D. R. Lynch
Selective Activation Induced Cleavage of the NR2B Subunit by Calpain
J. Neurosci., December 10, 2003; 23(36): 11322 - 11331.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics.