Metabotropic glutamate receptor 1-induced upregulation of NMDA receptor current: mediation through the Pyk2/Src-family kinase pathway in cortical neurons.
The mechanism underlying the upregulation of NMDA receptor function by group I metabotropic glutamate receptors (mGluRs), including mGluR1 and 5, is not known. Here we show that in cortical neurons, brief selective activation of group I mGluRs with (S)-3,5-dihydroxy-phenylglycine (DHPG) induced a Ca(2+)-calmodulin-dependent activation of Pyk2/CAKbeta and the Src-family kinases Src and Fyn that was independent of protein kinase C (PKC). Activation of Pyk2 and Src/Fyn kinases led to increased tyrosine phosphorylation of NMDA receptor subunits 2A and B (NR2A/B) and was blocked by a selective mGluR1 antagonist, 7-(hydroxyamino)cyclopropa[b]chromen-1a-carboxylate ethyl ester, but not an mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine. Functional linkage between mGluR1 activation and NR2A tyrosine phosphorylation through Pyk2 and Src was also demonstrated after expression of these elements in human embryonic kidney 293 cells. Supporting functional consequences, selective activation of mGluR1 by DHPG induced a potentiation of NMDA receptor-mediated currents that was blocked by inhibiting mGluR1 or Src-family kinases. Furthermore, antagonizing calmodulin or mGluR1, but not PKC, reduced the basal tyrosine phosphorylation levels of Pyk2 and Src, suggesting that mGluR1 may control the basal activity of these kinases and thus the tyrosine phosphorylation levels of NMDA receptors.
Heidinger
Valerie
V
Department of Neurology and Center for the Study of the Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Manzerra
Pat
P
Wang
Xue Qing
XQ
Strasser
Uta
U
Yu
Shan-Ping
SP
Choi
Dennis W
DW
Behrens
M Margarita
MM
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D004553:Electric Conductivity; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology*; D012118:Resorcinols / Q000494:pharmacology; D015398:Signal Transduction; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism*
D018690:Excitatory Amino Acid Agonists; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D011518:Proto-Oncogene Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D012118:Resorcinols; C104077:metabotropic glutamate receptor type 1; C079215:3,5-dihydroxyphenylglycine; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; D051418:Focal Adhesion Kinase 2; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D016392:Proto-Oncogene Proteins pp60(c-src); C496053:Ptk2b protein, mouse; D019061:src-Family Kinases; D005998:Glycine