Metabotropic glutamate receptor 1-induced upregulation of NMDA receptor current: mediation through the Pyk2/Src-family kinase pathway in cortical neurons. J Neurosci

Department of Neurology and Center for the Study of the Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 08/2002; 22(13):5452-61.
Source: PubMed

ABSTRACT 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.

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    • "6 5% , n 5 7 , P < 0 . 05 versus 2 - AG , Kruskal – Wallis rank sum test followed by the Bonferroni – Dunn multiple - comparison test ) ( Fig . 1C ) . Our lab has previously established that PKC can upregulate NMDAR mediated currents via Src family kinases ( SFKs ) ( Yang et al . , 2009 ; Yang et al . , 2012 ) . We therefore applied PP2 ( 1 lM ) ( Heidinger et al . , 2002 ) , a selective inhibitor of SFKs , in the patch pipette . In the presence of this inhibitor , 2 - AG failed to potentiate NMDAR function ( 2 - AG 1 PP2 : 94 . 7 6 5 . 3% , n5 6 , P < 0 . 05 versus 2 - AG , Kruskal – Wallis rank sum test followed by the Bonferroni – Dunn multiple - comparison test ) ( Fig . 1C ) . In contrast ,"
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    • "If mGluR5 serves as a bridge between PrP C and Fyn, then it is predicted to interact physically with both. We confirmed an association of mGluR5 with Fyn (Heidinger et al., 2002), and observed no alteration by PrP C or Abo (Figure S2A). Both mGluR1 and mGluR5 associate with Fyn, but mGluR8 does not (Figure S2B). "
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