Eph signaling regulates gliotransmitter release.

Astrocytes have been recently identified as important components of the tripartite synaptic complex. There is growing evidence that astrocytes regulate synaptic functions, in part, through the release of gliotransmitters. In a recent study, we have demonstrated that ephrinB3 could stimulate astrocytic release of D-serine through activation of EphB3 and EphA4 receptors. Eph receptors regulate this response by inducing the dephosphorylation of PKCα and activation of serine racemase to convert L-serine to D-serine. We now investigated whether ephrinB3 would increase the release of glutamine, which is also synthesized from serine and play important roles in regulating synaptic responses. Using HPLC, we observed an enhanced release of L/D-serine and glutamine from cultured astrocytes following ephrinB1 and/or ephrinB3 stimulation. In the absence of EphB3 and EphA4, ephrinB3-enhanced release of L/D-serine and glutamine was not observed. These studies provide evidence that Eph receptors may play broader roles in regulating gliotransmitter release from astrocytes, which could have important implications on synaptic transmission, and learning and memory processes.