PACAP(38) 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 (PACAP(38)) on N-methyl-D-aspartate (NMDA) receptor activity in cultured chick cortical neurons. Biphasic concentration-dependent effects of PACAP(38) on channel opening frequency induced by NMDA (20 mu M) and glycine(1 mu M) were found, with low concentrations (0.5-2 nM) of PACAP(38) increasing activity and higher concentrations ( 10-1,000 nM) causing inhibition. These effects were reversible, reduced with higher concentrations of glycine (2-10 mu M) but not by 200 mu M NMDA, and inhibited by 10 mu M 7-chlorokynurenic acid. In addition, 1 mu M PACAP(6-38) (a PACAP antagonist) inhibited channel activity due to 20 mu M NMDA and 1 mu M glycine by 66%, and this inhibition was reduced to 13% in the additional presence of 2 nM PACAP(38). These observations suggest that PACAP(38) 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).