PACAP, VIP, and PHI: effects on AC-, PLC-, and PLD-driven signaling systems in the primary glial cell cultures

Pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), and peptide histidine-isoleucine (PHI) are members of a superfamily of structurally related peptides widely distributed in the body and displaying pleiotropic biological activities. All these peptides are known to act via common receptors-VPAC1 and VPAC2. In addition, the effects of PACAP are mediated through its specific receptor named PAC1. The main signal transduction pathway of the mentioned receptors is adenylyl cyclase (AC)-->cAMP system. PACAP and VIP may also signal through receptor-linked phospholipase C (PLC)-->IP3/DAG-->PKC and phospholipase D (PLD)-->phosphatidic acid (PA) pathways. In the present article, we have studied the effects of PACAP, VIP, and PHI (0.001-5000 nM) on the AC-, PLC-, and PLD-driven signaling pathways in rat primary glial cell (astrocytes) cultures. All tested peptides dose-dependently and strongly stimulated cyclic adenosine 3',5'-monophosphate (cAMP) production in this experimental model, displaying the following rank order of potency: PACAP >> VIP > or = PHI. Their effects on PLC-IP3/DAG were weaker, while only PACAP and VIP (0.1-5 microM) significantly stimulated PLD activity. The obtained results showed that rat cerebral cortex-derived astrocytes are responsive to PACAP, VIP and PHI/PHM and possess PAC1 and likely VPAC-type receptors linked to activation of AC-cAMP-, PLC-IP3/DAG-, and PLD-PA signaling systems.