NMDA-induced currents receptors

In order to confirm the possible interaction of ethanol and crocin on NMDA receptors, we also performed whole-cell patch recording with primary cultured hippocampal neurons and measured membrane currents induced by the application of NMDA in a voltage-clamped condition. Application of 100 pM NMDA induced an inward current of 100.2 9.8 pA (n=10) at a holding potential of -60 mV. The NMDA-induced inward current was not affected by 10 pM CNQX (data not shown), but was completely abolished by 30 pM APV, supporting the fact that the response was mediated by NMDA receptors. Ethanol inhibited NMDA-induced currents in a concentration-dependent manner. Crocin (10 pM) had no effect on NMDA-induced currents by itself (data not shown), but attenuated the inhibitory effect of ethanol on NMDA-induced currents. The concentration-effect curve for ethanol was shifted to the right by the presence of crocin [22]. 

Redox phenomena seem to modulate activity of the NMDA subtype of glutamate receptors. Ascorbic acid inhibits binding of [ H]glutamate to the NMDA-receptor complex and impedes NMDA-gated currents in isolated neurons, whereas dithiothreitol-like reductants enhance NMDA-induced currents (Majewska et aL, 1990). The ability of reductants to alter function of the NMDA receptors is prevented by oxidation. This inhibitory effect of ascorbic acid on NMDA receptors may act to protect against excitotoxic insults to the neurons (Section 6). 

Hollmann, M., Boulter, J., Maron, C Beasley, L Sullivan, J., Pecht, G., and Heinemann, S. (1993) Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor. Neuron 10,943-954. 

P. Rossi et al.. Differential long-lasting potentiation of the NMDA and non-NMDA synaptic currents induced by metabotropic and NMDA receptor coactivation in cerebellar granule celts. Eur. J. Neurosci.. 8 (1996) 1182-1189. 

SSR-504734 is a potent, selective, and reversible inhibitor (IC50 = 18 nM) that is competitive with glycine [47,51]. The inhibitor rapidly and reversibly blocked the uptake of [14C]glycine in mouse cortical homogenates, which was sustained for up to 7 h. Complete cessation of blockade and return to glycine basal levels occurred prior to 24 h, which is in stark contrast to NFPS (>24 h). SSR-504734 potentiated a nearly twofold increase of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices and produced an increase in contralateral rotations in mice when microinjected into the striatum. Microdialysis experiments indicated that the inhibitor induced a rapid and sustained increase in extracellular glycine levels in the PFC of freely moving rats [51]. The compound also demonstrated efficacy in a variety of psychosis models [51-53]. SSR-504734 was reportedly in clinical trials for schizophrenia but discontinued after Phase I (data not disclosed) [54]. 

Heidinger V, Manzerra P, Wang XQ, Strasser U, Yu SP, et al. 2002. Metabotropic glutamate receptor 1-induced upregu-lation of NMDA receptor current Mediation through the Pyk2/Src-family kinase pathway in cortical neurons. J Neu-rosci 22 5452-5461. 

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