Modulation of protein tyrosine phosphatase activity alters the subunit assembly in native N-methyl-D-aspartate receptor complex.
The N-methyl-D-aspartate (NMDA) receptor is crucial for development and neuroplasticity as well as excitotoxicity. The biochemical basis of the disassembly and reassembly of NMDA receptor has never been reported. Using coimmunoprecipitation, Western blotting, and mass spectrometry, we show that inhibition of tyrosine phosphatases triggers disassembly of NR1, NR2A, and NR2B in cortical NMDA receptor complexes. Furthermore, the disassembly of the NMDA receptor subunits is immediate, dose-dependent, and reversible and seems to occur through mechanisms linked to Src kinases. Together, these results define a novel role for tyrosine phosphatases in the complex mechanism of NMDA receptor regulation.
Ferrani-Kile
Karima
K
Division of Pharmacology and Toxicology, College of Pharmacy and the Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, 1 University Station, A1915, Austin, TX 78712, USA. ferrani@mail.utexas.edu
Leslie
Steven W
SW
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D009474:Neurons / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D014443:Tyrosine / Q000378:metabolism; D014638:Vanadates / Q000633:toxicity; D019061:src-Family Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D013778:Tetrazolium Salts; D013844:Thiazoles; D014638:Vanadates; D014443:Tyrosine; D019061:src-Family Kinases; D017027:Protein Tyrosine Phosphatases; C022616:thiazolyl blue