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Two distinct modalities of NMDA‐receptor inactivation induced by calcium influx in cultured rat hippocampal neurons
Author(s) -
Schinder Alejandro F.,
Montal Mauricio
Publication year - 1993
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(93)80480-i
Subject(s) - hippocampal formation , nmda receptor , chemistry , calcium , biophysics , neuroscience , receptor , microbiology and biotechnology , biochemistry , biology , organic chemistry
Repetitive stimulation of glutamate (glu) receptors elicits increasingly smaller ionic currents in hippocampal neurons. To investigate mechanisms underlying this phenomenon, voltage clamp whole‐cell currents evoked by glu (100 μM) were recorded from hippocampal neurons in culture. These currents were primarily carried by N ‐methyl‐ d ‐aspartate‐receptor (NMDA‐R) channels, as shown by the voltage‐dependent sensitivity to extracellular Mg 2+ blockade, and inhibition by the specific antagonist MK‐801. In the presence of 2.2 mM extracellular Ca 2+ ([Ca 2+ ] e , repetitive glu applications (15 episodes of 4 s/min) elicited progressively smaller currents that stabilized at 45% of their initial peak value. Replacement of [Ca 2+ e , by Ba 2+ produced similar effects. This phenomenon, defined as interepisode inactivation , was exacerbated by elevating [Ca 2+ ] e to 11 mM, attenuated by reducing [Ca 2+ e to 0.22 mM, and further diminished by shortening the length of the glu pulse to 2 s. Current decay exhibited during individual stimuli, or intraepisode inactivation , was dependent on [Ca 2+ ] e yet remained stable during repetitive stimulation. We conclude that interepisode and intraepisode inactivations of NMDA‐R currents are the expression of two distinct processes triggered by Ca 2+ . These modalities of inactivation may arise from Ca 2+ binding either to the receptor or to closely associated regulatory proteins.