Herpesvirus quiescence in neuronal cells IV*: Virus activation induced by pituitary adenylate cyclase-activating polypeptide (PACAP) involves the protein kinase A pathway

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a naturally o ccurring peptide found in the central nervous system that plays a role in s omatosensory processing and activation of protein kinase A (PKA) and protei n kinase C (PKC), Because activation of PKA or PKC results in reactivation of HSV-1 from latently infected embryonic neuronal cells, PACAP was used to evaluate HSV-1 activation from quiescently infected (QIF)-PC12 cells. Our studies demonstrate that physiologically relevant concentrations of PACAP38 and PACAP27 induce HSV-1 activation from QIF-PC12 cell cultures in a dose- dependent fashion. PACAP-induced activation of virus was significantly impa ired by the PKA-inhibitor, H-89 (20 muM), whereas treatment with the PKC-in hibitor, GF109203X (1 muM), was without affect. Additionally, direct activa tion of PKA with cAMP analogs, 8-(4-chlorophenylthio)- and dibutyryl-cAMP o nly partially mimicked the effect of PACAP on virus activation. Taken toget her, PACAP induced HSV-1 activation from QIF-PC12 cells involves the PKA an d possibly cAMP-independent pathways. This report is the first to demonstra te that PACAP induces HSV-1 activation from a quiescent state and that this in vitro cell model is useful for studying early inductive events that lea d to virus production from quiescence.