PACAP38 modulates activity of NMDA receptors in cultured chick cortical neurons

The outside-out recording mode of the patch-clamp technique was used to study modulatory effects of pituitary adenylate cyclase-activating polypeptide (PACAP38) on N-methyl--aspartate (NMDA) receptor activity in cultured chick cortical neurons. Biphasic concentration-dependent effects of PACAP38 on channel opening frequency induced by NMDA (20 microM) and glycine (1 microM) were found, with low concentrations (0.5-2 nM) of PACAP38 increasing activity and higher concentrations (10-1,000 nM) causing inhibition. These effects were reversible, reduced with higher concentrations of glycine (2-10 microM) but not by 200 microM NMDA, and inhibited by 10 microM 7-chlorokynurenic acid. In addition, 1 microM PACAP6-38 (a PACAP antagonist) inhibited channel activity due to 20 microM NMDA and 1 microM glycine by 66%, and this inhibition was reduced to 13% in the additional presence of 2 nM PACAP38. These observations suggest that PACAP38 has a direct modulatory effect on the NMDA receptor that is independent of intracellular second messengers and probably mediated through the glycine coagonist site(s).