title: Two distinct modalities of NMDA-receptor inactivation induced by calcium influx in cultured rat hippocampal neurons.
abstract: 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.
authors.affiliation: Department of Biology, University of California San Diego, La Jolla 92093-0319.
authors.forename: A F
authors.initials: AF
authors.lastname: Schinder
authors.forename: M
authors.initials: M
authors.lastname: Montal
mesh_terms: 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
chemical_list: D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D001464:Barium; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D002118:Calcium