D-Serine inhibits AMPA receptor-mediated current in rat hippocampal neurons.
D-Serine, a recently identified gliotransmitter, serves as an endogenous coagonist binding to the glycine site of N-methyl-D-aspartate (NMDA) receptors. However, it is not clear whether this native ligand is able to bind to and modulate alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) receptors. In the present study, we showed that D-serine was able to concentration-dependently inhibit kainate-induced AMPA receptor-mediated current in acutely isolated hippocampal neurons. The blocking action of D-serine on AMPA receptors was characterized by a shift in concentration-response curve of kainate-induced current to the right with no change in the maximal response and independent of holding potential in the range of -80 to +60 mV. This is consistent with a model that D-serine is a competitive antagonist on AMPA receptors. In contrast, L-serine did not exert such an inhibitory action. Consistent with this observation, we found that several D-isoforms, but not L-isoforms, of endogenous and exogenous amino acids were able to block AMPA receptors. These results indicate that there is a low affinity and stereo-selective site at the agonist binding pocket of AMPA receptors for these D-amino acids. More importantly, vesicular-released endogenous D-serine from astrocytes could potentially modulate AMPA receptors in synaptic transmission in hippocampus.
Gong
Xiang-Qun
XQ
Department of Physiology and Pharmacology, University of Western Ontario, London, ON N6A 5C1, Canada.
Zabek
Rebecca L
RL
Bai
Donglin
D
D000200:Action Potentials / Q000187:drug effects*; D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology; D000613:Aminobutyrates / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007608:Kainic Acid / Q000494:pharmacology; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D012694:Serine / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology; D013237:Stereoisomerism; D014633:Valine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
D000596:Amino Acids; D000613:Aminobutyrates; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D012694:Serine; D016291:Dizocilpine Maleate; C056639:2-amino-5-phosphopentanoic acid; C012729:2-amino-4-phosphonobutyric acid; D014633:Valine; D007608:Kainic Acid