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 α-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.