期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 34, 期 2, 页码 199-212出版社
WILEY
DOI: 10.1111/j.1460-9568.2011.07768.x
关键词
cobalt; magnesium; manganese; NR2B; temperature-dependence; zinc
资金
- Korea Science and Engineering Foundation
- Cambridge Overseas Trust
- European Community
- Daiwa Anglo-Japanese Foundation
The N-methyl-d-aspartate receptor (NMDAR) exhibits strong voltage-dependent block by extracellular Mg2+, which is relieved by sustained depolarization and glutamate binding, and which is central to the function of the NMDAR in synaptic plasticity. Rapid membrane depolarization during agonist application reveals a slow unblock of NMDARs, which has important functional implications, for example in the generation of NMDAR spikes, and in determining the narrow time window for spike-timing-dependent plasticity. However, its mechanism is still unclear. Here, we study unblock of divalent cations in native NMDARs in nucleated patches isolated from mouse cortical layer 2/3 pyramidal neurons. Comparing unblock kinetics of NMDARs in the presence of extracellular Mg2+ or in nominally zero Mg2+, and with Mn2+ or Co2+ substituting for Mg2+, we found that the properties of slow unblock were determined by the identity of the blocking metal ion at the binding site, presumably by affecting the operation of a structural link to channel gating. The time course of slow unblock was not affected by zinc, or the zinc chelator TPEN [N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine], while the slower fraction of unblock was reduced by ifenprodil, an NR2B-selective antagonist. Slow unblock was only weakly temperature dependent, speeding up with rise in temperature with a Q(10) of approximate to 1.5. Finally, using action potential waveform voltage-clamp, we show that this slow relief from divalent cation block is a prominent feature in physiologically realistic patterns of changing membrane potential.
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