Gain control of N-methyl-D-aspartate receptor activity by receptor-like protein tyrosine phosphatase alpha.
Src kinase regulation of N-methyl-D-aspartate (NMDA) subtype glutamate receptors in the central nervous system (CNS) has been found to play an important role in processes related to learning and memory, ethanol sensitivity and epilepsy. However, little is known regarding the mechanisms underlying the regulation of Src family kinase activity in the control of NMDA receptors. Here we report that the distal phosphatase domain (D2) of protein tyrosine phosphatase alpha (PTPalpha) binds to the PDZ2 domain of post-synaptic density 95 (PSD95). Thus, Src kinase, its activator (PTPalpha) and substrate (NMDA receptors) are linked by the same scaffold protein, PSD95. Removal of PTPalpha does not affect the association of Src with NMDA receptors, but turns off the constitutive regulation of NMDA receptors by the kinase. Further more, we found that application of the PTPalpha catalytic domains (D1 + D2) into neurones enhances NMDA receptor-mediated synaptic responses. Conversely, the blockade of endogenous PTPalpha inhibits NMDA receptor activity and the induction of long-term potentiation in hippocampal neurones. Thus, PTPalpha is a novel up-regulator of synaptic strength in the CNS.
Lei
Gang
G
Center for Addiction and Mental Health, Faculty of Dentistry and Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T 1R8, Canada.
Xue
Sheng
S
Chéry
Nadège
N
Liu
Qiang
Q
Xu
Jindong
J
Kwan
Chun L
CL
Fu
Yang-Ping
YP
Lu
You-Ming
YM
Liu
Mingyao
M
Harder
Kenneth W
KW
Yu
Xian-Min
XM
D000818:Animals; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D005347:Fibroblasts / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D017774:Long-Term Potentiation / Q000502:physiology; D008565:Membrane Proteins; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C033652:postsynaptic density proteins; D019061:src-Family Kinases; D017027:Protein Tyrosine Phosphatases