Magnesium gates glutamate-activated channels in mouse central neurones

Abstract

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 sensitivity^2–6. Above resting potential, the current induced by a given dose of glutamate (or NMDA) increases when the cell is depolarized^4–6. 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 depolarization^4–6. 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’.