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 occurring peptide found in the central nervous system that plays a role in somatosensory processing and activation of protein kinase A (PKA) and protein 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 impaired by the PKA-inhibitor, H-89 (20 microM), whereas treatment with the PKC-inhibitor, GF109203X (1 microM), was without affect. Additionally, direct activation of PKA with cAMP analogs, 8-(4-chlorophenylthio)- and dibutyryl-cAMP, only partially mimicked the effect of PACAP on virus activation. Taken together, PACAP induced HSV-1 activation from QIF-PC12 cells involves the PKA and possibly cAMP-independent pathways. This report is the first to demonstrate 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 lead to virus production from quiescence.
Danaher
R J
RJ
Department of Oral Health Practice, University of Kentucky College of Dentistry and College of Medicine, Lexington, Kentucky 40536-0297, USA.
Savells-Arb
A D
AD
Black
S A
SA
Jacob
R J
RJ
Miller
C S
CS
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020803:Encephalitis, Herpes Simplex / Q000378:metabolism* / Q000821:virology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000254:growth & development*; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000821:virology*; D009479:Neuropeptides / Q000378:metabolism* / Q000494:pharmacology; D016716:PC12 Cells; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051381:Rats; D013449:Sulfonamides; D013873:Thionucleotides / Q000494:pharmacology; D017735:Virus Latency / Q000187:drug effects
C495403:Adcyap1 protein, rat; D004791:Enzyme Inhibitors; D007211:Indoles; D007546:Isoquinolines; D008301:Maleimides; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D013449:Sulfonamides; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D003994:Bucladesine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C070515:bisindolylmaleimide I; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide