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.
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.
Rácz
Boglárka
B
Department of Surgical Research and Techniques, University of Pecs, Hungary. boglarka.racz@aok.pte.hu
Gallyas
Ferenc
F
Kiss
Péter
P
Tamás
Andrea
A
Lubics
Andrea
A
Lengvári
István
I
Röth
Erzsébet
E
Tóth
Gábor
G
Hegyi
Orsolya
O
Verzál
Zsófia
Z
Fabricsek
Csaba
C
Reglódi
Dóra
D
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*
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