Two distinct modalities of NMDA-receptor inactivation induced by calcium influx in cultured rat hippocampal neurons.
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 microM) 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 Mg2+ blockade, and inhibition by the specific antagonist MK-801. In the presence of 2.2 mM extracellular Ca2+ ([Ca2+]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 [Ca2+]e by Ba2+ produced similar effects. This phenomenon, defined as interepisode inactivation, was exacerbated by elevating [Ca2+]e to 11 mM, attenuated by reducing [Ca2+]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 [Ca2+]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 Ca2+. These modalities of inactivation may arise from Ca2+ binding either to the receptor or to closely associated regulatory proteins.
Schinder
A F
AF
Department of Biology, University of California San Diego, La Jolla 92093-0319.
Montal
M
M
D000293:Adolescent; D000818:Animals; D001464:Barium / Q000378:metabolism; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005260:Female; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000187:drug effects
D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D001464:Barium; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D002118:Calcium