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

Acidic amino acids are putative excitatory synaptic transmitters ^1,2, 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^3,4, which in turn are coupled to separate conductance mechanisms⁵. N-methyl-D-aspartic acid (NMDA) is a selective agonist for one of these receptors^3,4. 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^6-9. Recently, patch-clamp experiments have shown the voltage-dependent block by Mg²⁺ of current flow through ion channels activated by L-glutamate¹⁰. 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 (∼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.