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 ,UM), (S)-3,5-dihydroxyphenylglycine (S-DHPG; 100,UM) and other mGluR agonists: (lS,3R)-1-aminocyclopentane-1,3-decarboxylic acid (1S,3R-ACPD; 200 uM), quisqualate (10 /M) and (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I; 100 AM). 3. The attenuation of NMDA current by 3HPG was totally eliminated by the mGluR antagonist (RS)-a-methyl-4-carboxyphenylglycine (MCPG; 500,FM) and by the selective mGluR1/5 antagonist (S)4-carboxyphenylglycine (4CPG; 300 FM). 4. mGluR2/3 agonists (2S,1'R,2'R'3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; 3,M), (S)4-carboxy-3-hydroxyphenylglycine (4C3HPG; 100-200 FM) and (S)4-carboxyphenyl- glycine (4CPG; 300 FM) did not reduce NMDA current. 5. The NMDA-induced increase in intracellular free Ca2' measured by fura-2 Ca2P imaging was attenuated by 3HPG (300 FM). 6. The suppression of NMDA current by 3HPG was not affected by treatments that altered intracellular Ca2P or cAMP levels, or by the protein kinase inhibitor, staurosporine (0'1-0-5 FM). 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,8S (200-400 FM). Intracellular dialysis of GTPyS (100 FM) 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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