Endogenous H+ modulation of NMDA receptor-mediated EPSCs revealed by carbonic anhydrase inhibition in rat hippocampus.
1. The occurrence of extracellular alkaline transients during excitatory synaptic transmission suggests that the NMDA receptor H(+)-modulatory site may have a physiological role. Here we amplify these pH shifts using benzolamide (a carbonic anhydrase inhibitor) and describe concomitant effects on EPSCs in whole-cell clamped CA1 neurones in rat hippocampal slices. 2. In CO2-HCO3(-)-buffered media, benzolamide increased the time to 50% decay (t50) of the EPSCs by 78 +/- 14% (P < 0.01, n = 10). This occurred simultaneously with amplification of the extracellular alkaline shift (154 +/- 14%). 3. In CO2-HCO3(-)-buffered media containing DL-2-amino-5-phosphonovalerate (APV), the EPSC t50 was unaltered by benzolamide, while the extracellular alkaline shifts were increased (111 +/- 23%, n = 8). 4. In Hepes-buffered media, neither the EPSC t50 nor the extracellular alkaline shift was altered by benzolamide (n = 9). 5. These data demonstrate that NMDA receptor activity is dependent on the buffering kinetics of the brain extracellular space. The results suggest that endogenous pH shifts can modulate NMDA receptor function in a physiologically relevant time frame.
Gottfried
J A
JA
Department of Physiology & Biophysics, New York University Medical Center, NY 10016.
Chesler
M
M
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001574:Benzolamide / Q000494:pharmacology; D001639:Bicarbonates / Q000494:pharmacology; D002021:Buffers; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D003470:Culture Media; D006624:Hippocampus / Q000201:enzymology / Q000502:physiology*; D006859:Hydrogen / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000502:physiology; D009412:Nerve Fibers / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
D001639:Bicarbonates; D002021:Buffers; D002257:Carbonic Anhydrase Inhibitors; D003470:Culture Media; D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D015763:2-Amino-5-phosphonovalerate; D006859:Hydrogen; D001574:Benzolamide