The effects of PACAP on neural cell proliferation.

PACAP and its receptors are expressed in growth zones of the brain. By stimulating PAC(1)-receptors PACAP can enhance, as well as reduce, the proliferation rate in a cell-type dependent manner. PACAP can enhance the proliferation rate by activating phospholipase C and protein kinase C, although other signal transduction pathways may also be responsible. PACAP can suppress proliferation by inhibiting protein complexes of the cyclins D and E with the cyclin-dependent kinases 4/6 and 2, respectively, which are necessary for entry into the cell cycle. PACAP seems to exert these inhibitory effects by acting via the Sonic hedgehog glycoprotein and the small GTPase RhoA. Also, the activation of a cyclin-dependent kinase inhibitor has been suggested. The signal transduction pathways mediating the effects of PACAP on proliferation are discussed.