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Magnesium gates glutamate-activated channels in mouse central neurones


The responses of vertebrate neurones to glutamate involve at least three receptor types1. One of these, the NMDA receptor (so called because of its specific activation by N-methyl-D-aspartate), induces responses presenting a peculiar voltage sensitivity2–6. Above resting potential, the current induced by a given dose of glutamate (or NMDA) increases when the cell is depolarized4–6. This is contrary to what is observed at classical excitatory synapses, and recalls the properties of ‘regenerative’ systems like the Na+ conductance of the action potential. Indeed, recent studies of L-glutamate, L-aspartate and NMDA-induced currents have indicated that the current–voltage (I–V) relationship can show a region of ‘negative conductance’ and that the application of these agonists can lead to a regenerative depolarization4–6. Furthermore, the NMDA response is greatly potentiated by reducing the extracellular Mg2+ concentration ([Mg2+]o) below the physiological level (1 mM)7,8. By analysing the responses of mouse central neurones to glutamate using the patch-clamp technique9, we have now found a link between voltage sensitivity and Mg2+ sensitivity. In Mg2+-free solutions, L-glutamate, L-aspartate and NMDA open cation channels, the properties of which are voltage independent. In the presence of Mg2+, the single-channel currentsmeasured at resting potential are chopped in bursts andthe probability of opening of the channels is reduced. Both effects increase steeply with hyper-polarization, thereby accounting for the negative slope of the I–V relationship of the glutamate response. Thus, the voltage dependence of the NMDA receptor-linked conductance appears to be a consequence of the voltage dependence of the Mg2+ block and its interpretation does not require the implication of an intramembrane voltage-dependent ‘gate’.

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Nowak, L., Bregestovski, P., Ascher, P. et al. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307, 462–465 (1984).

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