title: A presynaptic N-methyl-D-aspartate autoreceptor in rat hippocampus modulating amino acid release from a cytoplasmic pool.
abstract: A possible role of the N-methyl-D-aspartate receptor (NMDA-R) as a presynaptic autoreceptor was investigated using Percoll-purified hippocampus nerve terminals (synaptosomes). This preparation contained only a neglectable amount of postsynaptic structures. Two main effects of NMDA were observed. First, NMDA dose-dependently (10-100 microM) and in the absence of Mg2+, stimulated basal release of aspartate and glutamate, but not of GABA. MK801 (10 microM), an open NMDA-R-channel blocker, reduced this effect even below control levels, indicating endogenous NMDA-R activation. By superfusing synaptosomes, which prevents a tonic receptor occupation, also basal GABA release was stimulated by NMDA. The NMDA-induced potentiation of amino acid superfusate levels was blocked both by MK801 and Mg2+ (1 mM), was slow in onset and returned to baseline after NMDA-removal. The NMDA-effect was also found in the absence of extracellular Ca2+, suggesting that amino acids were released from a non-vesicular (cytoplasmic) pool. Secondly, in KCl-depolarized synaptosomes exposed to 1 mM Mg2+, NMDA did not affect the release of the amino acids. MK801, however, reduced the KCl-evoked Ca2+-independent release of aspartate and glutamate, but not of GABA. L-trans-PDC, the selective inhibitor of the glutamate/aspartate transporter, prevented this MK801-effect, suggesting a coupling between NMDA-Rs and these transporters. These data provide evidence for a presynaptic NMDA autoreceptor in rat hippocampus. We speculate on the role of this NMDA-R to depolarize the presynaptic membrane by Na+-entry, which may induce reversal of amino acid transporters and thereby releasing amino acids from a cytoplasmic pool.
authors.affiliation: Graduate School Neurosciences, Institute for Neurobiology, University of Amsterdam, The Netherlands.
authors.forename: A I
authors.initials: AI
authors.lastname: Breukel
authors.forename: E
authors.initials: E
authors.lastname: Besselsen
authors.forename: F H
authors.initials: FH
authors.lastname: Lopes da Silva
authors.forename: W E
authors.initials: WE
authors.lastname: Ghijsen
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D017660:Autoreceptors / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008854:Microscopy, Electron; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000737:chemistry* / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013574:Synaptosomes / Q000737:chemistry / Q000648:ultrastructure; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D017660:Autoreceptors; D018691:Excitatory Amino Acid Antagonists; D018377:Neurotransmitter Agents; D016194:Receptors, N-Methyl-D-Aspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; D016291:Dizocilpine Maleate; D008274:Magnesium; D002118:Calcium