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J Physiol. 1997 Mar 15;499 ( Pt 3):721-32.

Membrane-delimited modulation of NMDA currents by metabotropic glutamate receptor subtypes 1/5 in cultured mouse cortical neurons.

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Centre for the Study of Nervous System Injury, Washington University School of Medicine, St Louis, MO 63110, USA.


1. Modulation of NMDA receptors by metabotropic glutamate receptors (mGluRs) in cultured mouse cortical neurons was investigated using whole-cell and single-channel recordings. 2. NMDA whole-cell current was reversibly attenuated by selective mGluR1/5 agonists (S)-3-hydroxyphenylglycine (3HPG; 10-200 microM), (S)-3,5-dihydroxyphenylglyeine (S-DHPG; 100 microM) and other mGluR agonists: (1S,3R)-1-aminocyclopentane-1,3-decarboxylic acid (1S,3R-ACPD; 200 microM), quisqualate (10 microM) and (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I; 100 microM). 3. The attenuation of NMDA current by 3HPG was totally eliminated by the mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG; 500 microM) and by the selective mGluR1/5 antagonist (S)-4-carboxyphenylglycine (4CPG; 300 microM). 4. mGluR2/3 agonists (2S,1'R,2'R'3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; 3 microM), (S)-4-carboxy-3-hydroxyphenylglycine (4C3HPG; 100-200 microM) and (S)-4-carboxyphenylglycine (4CPG; 300 microM) did not reduce NMDA current. 5. The NMDA-induced increase in intracellular free Ca2+ measured by fura-2 Ca2+ imaging was attenuated by 3HPG (300 microM). 6. The suppression of NMDA current by 3HPG was not affected by treatments that altered intracellular Ca2+ or cAMP levels, or by the protein kinase inhibitor, staurosporine (0.1-0.5 microM). 7. The open probability (NPo) of the NMDA receptor channel in excised outside-out patches was attenuated by 3HPG but not by 4C3HPG. This 3HPG effect was blocked by MCPG. 8. The 3HPG-induced reduction of NMDA whole-cell and single-channel currents was prevented by GDP beta S (200-400 microM). Intracellular dialysis of GTP gamma S (100 microM) also reduced NMDA whole-cell current, and rendered irreversible further reduction induced by 3HPG. 9. These data suggest that a selective activation of mGluR1/5 downmodulates the NMDA receptor channel in a membrane-delimited manner, mediated by G proteins, but not by diffusible second messengers.

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