Contractor, Anis; (1997) Metabotropic glutamate receptor mediated modulation of N-methyl-D-aspartate (NMDA) receptor-channels in the rat hippocampus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

N-methyl-D-aspartate receptors (NMDARs) were studied in granule cells of the rat hippocampus using high resolution patch-clamp electrophysiological techniques. The opening behaviour of the receptor-channel was observed in experiments employing the cell-attached configuration in order not to disturb the intracellular contents and maintain the normal physiology of the cell. Co-activation of metabotropic glutamate receptors (mGluRs) located on the somatic membrane of these cells caused a robust and reproducible modulation in a number of the NMDARs single channel parameters. There was attenuation in the mean open time, burst length and cluster length of activation. Surprisingly there was also a decrease in the slope conductance of the receptor-channel. This mGluR mediated modulation was occluded by applying cyclosporin A (CsA) which specifically inhibits the intracellular phosphatase 2B (calcineurin). Whole-cell experiments employing the perforated patch configuration showed that mGluR activation could also attenuate whole-cell responses. However when the intracellular contents were disturbed either by using standard whole-cell techniques which cause washout of the cell or using fluoride (F') in the pipette to permeate the membrane and inhibit phosphatases, there was no predictable modulation of NMD A responses by mGluRs. Voltage ramps performed during application of NMD A to these cells in the presence of varying concentrations of Mg2+ failed to show that this mGluR mediated modulation caused any change in the dissociation equilibrium constant for Mg2+ (KMg) or the fraction of the voltage field the blocker senses. This suggests that there is no change in Mg2+ sensitivity of the NMDA receptor-channel due to mGluR mediated modulation. Preliminary experiments testing the divalent permeability of the NMDAR-channel suggested there might be a decrease in the divalent/monovalent permeability ratio (PD2+/PM+).

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