title: Effects of pituitary adenylate cyclase activating polypeptide (PACAP) on the PKA-Bad-14-3-3 signaling pathway in glutamate-induced retinal injury in neonatal rats.
abstract: The neuropeptide PACAP (pituitary adenylate cyclase activating polypeptide) and its receptors are widely expressed in the nervous system including the retina. PACAP has well-known neuroprotective effects in neuronal cultures in vitro and against different insults in vivo. Recently, we have shown that PACAP1-38 is neuroprotective against monosodium glutamate (MSG)-induced retinal degeneration. Studying the molecular mechanisms of this protection has revealed that PACAP1-38 stimulates anti-apoptotic mechanisms such as phosphorylation of ERK1/2 and inhibits pro-apoptotic signaling molecules such as JNK1/2, p38MAPK, caspase-3 and the translocation of mitochondrial cytochrome c and apoptosis inducing factor in glutamate-treated retinas in vivo. In the present study we investigated the effects of PACAP1-38 on a further signal transduction pathway possibly involved in the protective effect of intravitreal PACAP1-38 administration against apoptotic retinal degeneration induced by neonatal MSG treatment. The focus of the present study was the protein kinase A (PKA)-Bad-14-3-3 transduction pathway. In vivo MSG treatment led to a reduction in the levels of anti-apoptotic molecules (phospho-PKA phospho-Bad, Bcl-xL and 14-3-3 proteins) in the retina. Co-treatment with PACAP1-38 counteracted these effects: the level of phospho-PKA, phospho-Bad, Bcl-xL and 14-3-3 were increased. All effects of PACAP1-38 were inhibited by the PACAP antagonist PACAP6-38. In summary, our results show that PACAP1-38 activates the PKA-Bad-14-3-3 pathway which is inhibited by MSG treatment. Our results also provide new insights into the signaling mechanisms possibly involved in the PACAP-mediated anti-apoptotic effects.
authors.affiliation: Department of Surgical Research and Techniques, University of Pecs, Hungary. boglarka.racz@aok.pte.hu
authors.forename: Boglárka
authors.initials: B
authors.lastname: Rácz
authors.forename: Ferenc
authors.initials: F
authors.lastname: Gallyas
authors.forename: Péter
authors.initials: P
authors.lastname: Kiss
authors.forename: Andrea
authors.initials: A
authors.lastname: Tamás
authors.forename: Andrea
authors.initials: A
authors.lastname: Lubics
authors.forename: István
authors.initials: I
authors.lastname: Lengvári
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Röth
authors.forename: Gábor
authors.initials: G
authors.lastname: Tóth
authors.forename: Orsolya
authors.initials: O
authors.lastname: Hegyi
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Verzál
authors.forename: Csaba
authors.initials: C
authors.lastname: Fabricsek
authors.forename: Dóra
authors.initials: D
authors.lastname: Reglódi
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid; D008954:Models, Biological; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012164:Retinal Diseases / Q000139:chemically induced / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051025:bcl-Associated Death Protein / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D004791:Enzyme Inhibitors; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051025:bcl-Associated Death Protein; D018698:Glutamic Acid; D017868:Cyclic AMP-Dependent Protein Kinases