Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase‐Activating Polypeptide Potentiate c‐fos Expression Induced by Glutamate in Cultured Cortical Neurons

Abstract: Previous reports have demonstrated that glutamate stimulates c‐fos mRNA expression in primary cultures of mouse cerebral cortical neurons. We show here that vasoactive intestinal peptide (VIP) induces c‐fos mRNA expression; however, this effect of VIP is completely inhibited by the noncompetitive NMDA receptor antagonist MK‐801, therefore indicating that VIP stimulates c‐fos expression in a glutamate‐dependent manner. A similar effect was observed with pituitary adenylate cyclase‐activating polypeptide27 (PACAP27). At the intracellular level, coactivation of protein kinases A and C mediates the glutamate‐dependent stimulation of c‐fos expression evoked by VIP, because either H‐89 or staurosporin inhibits the effect of VIP as well as that of glutamate. These results point to a “biochemical AND gate” mechanism, which implies the obligatory activation of both protein kinases A and C in the transduction of c‐fos expression. In summary, this article provides evidence that VIP and PACAP27 potentiate the effect of glutamate, the principal effector on c‐fos expression, suggesting that both peptides can increase the “throughput” or “strength” of glutamate‐containing circuits in the cerebral cortex.