Ca(2+)-independent reduction of N-methyl-D-aspartate channel activity by protein tyrosine phosphatase.
Regulation of ion channel function by intracellular processes is fundamental for controlling synaptic signaling and integration in the nervous system. Currents mediated by N-methyl-D-aspartate (NMDA) receptors decline during whole-cell recordings and this may be prevented by ATP. We show here that phosphorylation is necessary to maintain NMDA currents and that the decline is not dependent upon Ca2+. A protein tyrosine phosphatase or a peptide inhibitor of protein tyrosine kinase applied intracellularly caused a decrease in NMDA currents even when ATP was included. On the other hand, pretreating the neurons with a membrane-permeant tyrosine kinase inhibitor occluded the decline in NMDA currents when ATP was omitted. In inside-out patches, applying a protein tyrosine phosphatase to the cytoplasmic face of the patch caused a decrease in probability of opening of NMDA channels. Conversely, open probability was increased by a protein tyrosine phosphatase inhibitor. These results indicate that NMDA channel activity is reduced by a protein tyrosine phosphatase associated with the channel complex.
Wang
Y T
YT
Division of Neuroscience, Hospital for Sick Children, Toronto, Canada.
Yu
X M
XM
Salter
M W
MW
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000266:Adenylyl Imidodiphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein; D015640:Ion Channel Gating / Q000187:drug effects*; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D007529:Isoflavones / Q000494:pharmacology; D015688:Oncogene Protein pp60(v-src) / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology
D004791:Enzyme Inhibitors; D007473:Ion Channels; D007529:Isoflavones; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; C098708:peptide A; D000266:Adenylyl Imidodiphosphate; C022571:adenosine 5'-O-(3-thiotriphosphate); D004533:Egtazic Acid; D000255:Adenosine Triphosphate; D019833:Genistein; D015688:Oncogene Protein pp60(v-src); D016392:Proto-Oncogene Proteins pp60(c-src); D017027:Protein Tyrosine Phosphatases; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium