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.

Protective Effect of PACAP Against Doxorubicin-Induced Cell Death in Cardiomyocyte Culture

“…In phosphorylated form, Bad binds to 14-3-3 protein, and in this form it is unable to inhibit the action of the antiapoptotic mitochondrial proteins. The stimulating effect of PACAP on Bad phosphorylation has been shown earlier in glutamate-induced retinal toxicity and also in cardiomyocytes (Racz et al 2007b(Racz et al , 2008.…”

Effects of PACAP in UV-A Radiation-Induced Retinal Degeneration Models in Rats

“…We have shown that PACAP is able to activate antiapoptotic signaling pathways while it inhibits pro-apoptotic molecules (Racz et al 2006). For example, PACAP induced the protective protein kinase A/Bad/14-3-3 protein pathway, stimulated the protective bcl-2 and bcl-xL mitochondrial proteins, and increased the expression of cAMP response element binding and extracellular signal-regulated kinase (Racz et al 2006(Racz et al , 2007. At the same time, it inhibited the expression of the pro-apoptotic apoptosis-inducing factor, c-jun N-terminal kinase, caspase-3, and the release of mitochondrial cytochrome c. Further mechanisms may also add to the protective effects of PACAP in the retina.…”

Ocular Delivery of PACAP1-27 Protects the Retina From Ischemic Damage in Rodents

“…It has antiapoptotic/antioxidant effects and promotes an anti-inflammatory status. [44][45][46][47] We have previously shown that PACAP, binding to its receptors present in the retina, stimulates antiapoptotic, whereas inhibits proapoptotic pathways, 17,44,45,48 including the pathways studied here: ERK1/2 and Akt. PACAP not only has strong antiapoptotic properties, but also has antiinflammatory and antioxidant actions.…”