Pituitary adenylate cyclase-activating polypeptide stimulates glial fibrillary acidic protein gene expression in cortical precursor cells by activating Ras and Rap1

Pituitary adenylate cyclase-activating polypeptide (PACAP) acts on cortical precursor cells to trigger glial fibrillary acidic protein (GFAP) gene expression and astrocyte differentiation by stimulation of intracellular cAMP production. Here, we show that as expected, PACAP activates cAMP-dependent protein kinase A. However, inhibition of protein kinase A does not prevent PACAP-induced GFAP gene expression or astrocytogenesis. PACAP also activates the small GTPases Rap1 and Ras, but either activation of Rap1 alone by selective stimulation of the guanine nucleotide exchange factor Epac, or expression of a constitutively active form of Ras, do not induce GFAP gene expression. Ras is activated by PACAP in a cAMP-dependent manner, and inhibition of Ras and/or Rap1 decreases PACAP-induced GFAP promoter stimulation. Thus, cAMP-dependent PACAP-induced GFAP expression during astrocytogenesis involves the coordinated activation of both Ras and Rap1, but activation of either one of them in isolation is not sufficient to trigger this response.