Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones

Abstract

Acidic amino acids are putative excitatory synaptic transmitters, the ionic mechanism of which is not well understood. Recent studies with selective agonists and antagonists suggest that neurones of the mammalian central nervous system possess several different receptors for acidic amino acids, which in turn are coupled to separate conductance mechanisms. N-methyl-D-aspartic acid (NMDA) is a selective agonist for one of these receptors. The excitatory action of amino acids acting at NMDA receptors is remarkably sensitive to the membrane potential and it has been suggested that the NMDA receptor is coupled to a voltage-sensitive conductance. Recently, patch-clamp experiments have shown the voltage-dependent block by Mg2+ of current flow through ion channels activated by L-glutamate. We now show using voltage-clamp experiments on mouse spinal cord neurones that the voltage-sensitivity of NMDA action is greatly reduced on the withdrawal of physiological concentrations (approximately 1 mM) of Mg2+ from the extracellular fluid. This provides further evidence that Mg2+ blocks inward current flow through ion channels linked to NMDA receptors.

Reduction of Infarct Volume by Magnesium after Middle Cerebral Artery Occlusion in Rats

“…It has been demonstrated that Mg 2 + binds to a site within the NMDA-gated ionophore (Nowak et al , 1984). The blocking of the NMDA receptor-associated channel by Mg 2 + is strongly voltage dependent (Mayer et al , 1984). However, the persistent phase of depolarization in duced by ischemic conditions in rat hippocampal slices is selectively blocked by lowering calcium and raising magnesium as well as by NMDA antag onists.…”

Effects of memantine and MK‐801 on NMDA‐induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices

“…The hypothesis of Parsons et al (1993) was made on the basis of the fact that NMDA receptors are activated physiologically by mM concentrations of synaptically-released glutamate which transiently strongly depolarize the postsynaptic membrane (Clements et al, 1992;Pongracz et al, 1992) whereas, even during acute excitotoxic insults like ischaemia, relatively low pM concentrations of interstitial glutamate cause only moderate membrane depolarization but for much longer periods of time (Benveniste et al, 1984;Globus et al, 1989;1991;Andine et al, 1991;Buisson et al, 1992;Mitani et al, 1992;Hashimoto et al, 1994). It is well accepted that the strong voltage-dependency and rapid unblocking kinetics of Mg2" (Nowak et al, 1984;Mayer et al, 1984) allow this cation to leave the NMDA receptor channel upon transient physiological activation during the induction of LTP. Indeed, precisely these properties make the NMDA receptor channel complex inherently suited for its role in mediating synaptic plasticity (Herron et al, 1986;Bliss & Collingridge, 1993).…”

Subtype-selective antagonism of N-methyl-d-aspartate receptor ion channels by synthetic conantokin peptides

“…The NMDAR is a ligand-gated neuronal ion channel, which, at resting membrane potentials, is blocked by Mg 2+ (Mayer et al, 1984). Channel opening occurs through binding of the coagonists, glutamate (or NMDA) and glycine (Jahr and Stevens, 1987;Johnson and Ascher, 1987).…”