Mediation by calcium/calmodulin-dependent protein kinase II of suppressionof GABA(A) receptors by NMDA

Using nystatin-perforated whole-cell recording configuration, the modulator y effect of N-methyl-D-aspartate (NMDA) on gamma -aminobutyric acid (GABA)- activated whole-cell currents was investigated in neurons freshly dissociat ed from the rat sacral dorsal commissural nucleus (SDCN). The results showe d that: (i) NMDA suppressed GABA- and muscimol (Mus)-activated currents (I- GABA and I-Mus) respectively in the Mg2+-free external solution containing 1 mu mol/L glycine at a holding potential (V-H) of -40 mV in SDCN neurons. The selective NMDA receptor antagonist, D-2-amino-5-phosphonovaleric acid ( APV, 100 mu mol/L), inhibited the NMDA-evoked currents and blocked the NMDA -induced suppression of I-GABA (ii) when the neurons were incubated in a Ca 2+-free bath or pre-loaded with a membrane-permeable Ca2+ chelator, BAPTA A M (10 mu mol/L), the inhibitory effect of NMDA on I-GABA disappeared. Cd2(10 mu mol/L) or La3+ (30 mu mol/L), the non-selective blockers of voltage- dependent calcium channels, did not affect the suppression of I-GABA by NMD A application; (iii) the suppression of I-GABA by NMDA was inhibited by KN- 62, a calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor. Th ese results indicated that the inhibition of GABA response by NMDA is Ca2+- dependent and CaMKII is involved in the process of the Ca2+-dependent inhib ition.