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The Journal of Neuroscience, July 1, 2002, 22(13):5452-5461
Metabotropic Glutamate Receptor 1-Induced Upregulation of NMDA
Receptor Current: Mediation through the Pyk2/Src-Family Kinase Pathway
in Cortical Neurons
Valérie
Heidinger,
Pat
Manzerra,
Xue Qing
Wang,
Uta
Strasser,
Shan-Ping
Yu,
Dennis
W.
Choi, and
M. Margarita
Behrens
Department of Neurology and Center for the Study of the Nervous
System Injury, Washington University School of Medicine, St. Louis,
Missouri 63110
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
Ca2+-calmodulin-dependent activation of Pyk2/CAK
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.
Key words:
NMDA; metabotropic; Pyk2/CAK; Src/Fyn; calmodulin; phosphorylation
Copyright © 2002 Society for Neuroscience 0270-6474/02/22135452-10$05.00/0
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