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 culturesin vitro and against different insultsin 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 antiapoptotic 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 cytochromec and apoptosis inducing factor in glutamate-treated retinasin 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.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Atlasz T, N Babai, P Kiss, D Reglodi, A Tamas, K Szabadfi, G Toth, O Hegyi, A Lubics and R Gabriel (2007) Pituitary adenylate cyclase activating polypeptide is protective in bilateral carotid occlusion-induced retinal lesion in rats.Gen. Comp. Endocrinol. 153, 108–114.
Aubert N, A Falluel-Morel, D Vaudry, X Xifro, J Rodriguez-Alvarez, C Fisch, S de Jouffreu, JF Lebigot, A Fournier, H Vaudry and BJ Gonzalez (2006) PACAP and C2-ceramide generate AP-1 complexes through a MAP-kinase-dependent pathway: involvement of c-Fos in PACAP-induced Bcl-2 expression.J. Neurochem. 99, 1237–1250.
Babai N, T Atlasz, A Tamas, D Reglodi, P Kiss and R Gabriel (2005) Degree of damage compensation by various PACAP treatments in monosodium glutamate-induced retina degeneration.Neurotox. Res. 8, 227–233.
Babai N, T Atlasz, A Tamas, D Reglodi, G Toth, P Kiss and R Gabriel (2006) Search for the optimal monosodium glutamate treatment schedule to study the neuroprotective effects of PACAP in the retina.Ann. NY Acad. Sci. 1070, 149–155.
Baptiste DC, AT Hartwick, CA Baltimore, WH Baldridge, GM Seigel and ME Kelly (2004) An investigation of the neuroprotective effects of tetracycline derivatives in experimental models of retinal cell death.Mol. Pharmacol. 66, 1113–1122.
Barkana Y and M Belkin (2004) Neuroprotection in ophthalmology: a review.Brain Res. Bull. 62, 447–453.
Borba JC, IP Henze, MS Silveira, RC Kubrusly, PF Gardino, MC de Mello, JN Hokoç and FG de Mello (2005) Pituitary adenylate cyclase activating polypeptide (PACAP) can act as determinant of the tyrosine hydoxylase phenotype of dopaminergic cells during retina development.Dev. Brain Res. 156, 193–201.
Castel H, D Vaudry, YA Mei, T Lefebvre, M Basille, L Desrues, A Fournier, H Vaudry, MC Tonon and BJ Gonzalez (2006) The delayed rectifier channel current IK plays a key role in the control of programmed cell death by PACAP and ethanol in cerebellar granule neurons.Ann. NY Acad. Sci. 1070, 173–179.
Charles I, A Khalyfa, DM Kumar, RR Krishnamoorthy, RS Roque, N Cooper and N Agarwal (2005) Serum deprivation induces apoptotic cell death of transformed rat retinal ganglion cells via mitochondrial signaling pathways.Invest. Ophthalmol. Vis. Sci. 46, 1330–1338.
Chen ST, IR Hsu, PC Hsu and JI Chuang (2003) The retina as a novelin vivo model for studying the role of molecules of the Bcl-2 family in relation to MPTP neurotoxicity.Neurochem. Res. 28, 805–814.
Chen TA, F Yang, GM Cole and SO Chan (2001) Inhibition of caspase-3-like activity reduces glutamate-induced cell death in the adult rat retina.Brain Res. 904, 177–188.
D Agata V and S Cavallaro (1998) Functional and molecular expression of PACAP/VIP receptors in the rat retina.Mol. Brain Res. 54, 161–164.
Datta SR, A Katsov, L Hu, A Petros, SW Fesik, MB Yaffe and ME Greenberg (2000) 14-3-3 proteins and survival kinases cooperate to inactivate Bad by BH3 domain phosphorylation.Mol. Cell 6, 41–51.
Dohi K, H Mizushima, S Nakajo, H Ohtaki, S Matsunaga, T Aruga and S Shioda (2002) Pituitary adenylate cyclase activating polypeptide (PACAP) prevents hippocampal neurons from apoptosis by inhibiting JNK/SAPK and p38 signal transduction pathways.Regul. Pept. 109, 83–88.
Doonan F and TG Cotter (2004) Apoptosis: a potential therapeutic target for retinal degenerations.Curr. Neurovasc. Res. 1, 41–53.
Falluel-Morel A, N Aubert, D Vaudry, M Basille, M Fontaine, A Fournier, H Vaudry and BJ Gonzalez (2004) Opposite regulation of the mitochondrial apoptotic pathway by C2-ceramide and PACAP through a MAP-kinase-dependent mechanism in cerebellar granule cells.J. Neurochem. 91, 1231–1243.
Falluel-Morel A, M Chafai, D Vaudry, M Basille, M Cazillis, N Aubert, E Louiset, S de Jouffrey, JF Le Bigot, A Fournier, P Gressens, W Rostene, H Vaudry and BK Gonzalez (2007) The neuropeptide pituitary adenylate cyclase activating polypeptide exerts anti-apoptotic and differentiating effects during neurogenesis: focus on cerebellar granule neurones and embryonic stem cells.J. Neuroendocrinol. 19, 321–327.
Gasz B, B Racz, E Roth, B Borsiczky, A Ferencz, A Tamas, B Cserepes, A Lubics, F Gallyas Jr, G Toth, I Lengvari and D Reglodi (2006a) Pituitary adenylate cyclase activating polypeptide protects cardiomyocytes against oxidative stress-induced apoptosis.Peptides 27, 87–94.
Gasz B, B Racz, E Roth, B Borsiczky, A Tamas, A Boronkai, F Gallyas Jr, G Toth and D Reglodi (2006b) PACAP inhibits oxidative stress-induced activation of MAP kinase dependent apoptotic pathway in cultured cardiomyocytes.Ann. NY Acad. Sci. 1070, 293–297.
Hannibal J and J Fahrenkrug (2004) Target areas innervated by PACAP-immunoreactive retinal ganglion cells.Cell Tissue Res. 316, 99–113.
Harada H, B Becknell, M Wilm, M Mann, LJ Huang, SS Taylor, JD Scott and SJ Korsmeyer (1999) Phosphorylation and inactivation of BAD my mitochondria-anchored protein kinase A.Mol. Cell 3, 413–422.
Izumi S, T Seki, S Shioda, CJ Zhou, A Arimura and R Koide (2000) Ultrastructural localization of PACAP immunoreactivity in the rat retina.Ann. NY Acad. Sci. 921, 317–320.
Jozsa R, A Somogyvari-Vigh, D Reglodi, T Hollosy and A Arimura (2001) Distribution and daily variations of PACAP in the chicken brain.Peptides 22, 1371–1317.
Kim HS and CK Park (2005) Retinal ganglion cell death is delayed by activation of retinal intrinsic cell survival program.Brain Res. 1057, 17–28.
Kiss P, A Tamas, A Lubics, I Lengvari, M Szalai, D Hauser, ZS Horvath, B Racz, R Gabriel, N Babai, G Toth and D Reglodi (2006) Effects of systemic PACAP treatment in monosodium glutamate-induced behavioral changes and retinal degeneration.Ann. NY Acad. Sci. 1070, 365–370.
Kostrzewa RM (1999) Selective neurotoxins, chemical tools to probe the mind: the first thirty years and beyond.Neurotox. Res. 1, 3–25.
Kubrusly RC, MC da Cunha, RA Reis, H Soares, AL Ventura, E Kurtenbach, MC de Mello and FG de Mello (2005) Expression of functional receptors and transmitter enzymes in cultured Muller cells.Brain Res. 1038, 141–149.
Lam TT, AS Abler, JM Kwong and MO Tso (1999)N-methyl-D-aspartate (NMDA)-induced apoptosis in rat retina.Invest. Ophthalmol. Vis. Sci. 40, 2391–2397.
Morio H, I Tatsuno, A Hirai, Y Tamura and Y Saito (1996) Pituitary adenylate cyclase activating polypeptide protects rat-cultured cortical nenrons from glutamate-induced cytotoxicity.Brain Res. 741, 82–88.
Munemasa Y, R Ohtani-Kaneko, Y Kitaoka, K Kurobayashi, K Isenoumi, J Kogo, K Yamashita, T Kumai, S Kobayashi, K Hirata and S Ueno (2005) Contribution of mitogen-activated protein kinases to NMDA-induced neurotoxicity in the rat retina.Brain Res. 1044, 227–240.
Nakatani M, T Seki, Y Shinohara, C Taki, S Nishimura, A Takaki and S Shioda (2006) Pituitary adenylate cyclase activating peptide (PACAP) stimulates production of interleukin-6 in rat Muller cells.Peptides 27, 1871–1876.
Onali P and MC Olianas (1994) PACAP is a potent and highly effective stimulator of adenylyl cyclase activity in the retinas of different mammalian species.Brain Res. 641, 132–134.
Racz B, A Tamas, P Kiss, G Toth, B Gasz, B Borsiczky, A Ferencz, F Gallyas Jr, E Roth and D Reglodi (2006a) Involvement of ERK and CREB signalling pathways in the protective effect of PACAP on monosodium glutamate-induced retinal lesion.Ann. NY Acad. Sci. 1070, 507–511.
Racz B, F Gallyas Jr, P Kiss, G Toth, O Hegyi, B Gasz, B Borsiczky, A Ferencz, E Roth, A Tamas, I Lengvari, A Lubics and D Reglodi (2006b) The neuroprotective effects of PACAP in monosodium glutamate-induced retinal lesion involves inhibition of proapoptotic signaling pathways.Regul. Pept. 137, 20–26.
Racz B, D Reglodi, P Kiss, N Bobai, T Atlasz, R Gabriel, A Lubics, F Gallyas Jr, B Gasz, G Toth, E Roth, O Hegyi, I Lengvari and A Tamas (2006c)In vivo neuroprotection by PACAP in excitotoxic retinal injury: review of effects on retinal morphology and apoptotic signal transduction.Int. J. Neuroprot. Neurodeg. 2, 80–85.
Racz B, B Gasz, B Borsiczky, F Gallyas Jr, A Tamas, R Jozsa, A Lubics, P Kiss, E Roth, A Ferencz, G Toth, O Hegyi, I Wittmann, I Lengvari, A Somogyvari-Vigh and D Reglodi (2007a) Protective effects of pituitary adenylate cyclase activating polypeptide in endothelial cells against oxidative stress-induced apoptosis.Gen. Comp. Endocrinol. 153, 115–123.
Racz B, B Gasz, F Gallyas Jr, P Kiss, A Tamas, R Jozsa, A Lubics, I Lengvari, G Toth, O Hegyi, E Roth and D Reglodi (2007b) PKA-Bad-14-3-3 and Akt-Bad-14-3-3 signaling pathways are involved in the protective effects of PACAP against ischemia/reperfusion-induced cardiomyocyte apoptosis.Regul. Pept. (in press).
Ravni A, S Bourgault, A Lebon, P Chan, L Galas, A Fournier, H Vaudry, B Gonzalez, LE Eiden and D Vaudry (2006) The neurotrophic effects of PACAP in PC12 cells: control by multiple transduction pathways.J. Neurochem. 98, 321–329.
Reglodi D, A Tamas, B Racz, V Denes, A Lubics, I Lengvari and R Gabrnel (2005) Effects of pituitary adenylate cyclase activating polypeptide in retinal degeneration induced by monosodium-glutamate in the rat.Neurotox. Res. 8, 324.
Said SI, K Dickman, RD Dey, A Bandyopadhyay, P De Stefanis, S Raza, H Pakbaz and HI Berisha (1998) Glutamate toxicity in the lung and neuronal cells: prevention or attenuation by VIP and PACAP.Ann. NY Acad. Sci. 865, 226–237.
Segura-Aguilar J and RM Kostrzewa (2004) Neurotoxins and neurotoxic species implicated in neurodegeneration.Neurotox. Res. 6, 615–630.
Segura-Aguilar J and RM Kostrzewa (2006) Neurotoxins and neurotoxicity mechanisms. An overview.Neurotox. Res. 10, 263–285.
Seki T, S Izumi, S Shioda, CJ Zhou, A Arimura and R Koide (2000a) Gene expression for PACAP receptor mRNA in the rat retina byin situ hybridization andin situ RT-PCR.Ann. NY Acad. Sci. 921, 366–369.
Seki T, S Shioda, S Izumi, A Arimura and R Koide (2000b) Electron microscopic observation of pituitary adenylate cyclase activating polypeptide (PACAP)-containing neurons in the rat retina.Peptides 21, 109–113.
Seki T, S Izumi, S Shioda and A Arimura (2003) Pituitary adenylate cyclase activating polypeptide (PACAP) protects ganglion cell death against cutting of optic nerve in the rat retina.Regul. Pept. 115, 55. Abstract.
Seki T, M Nakatani, C Taki, Y Shinohara, M Ozawa, S Nishimura, H Ito and S Shioda (2006) Neuroprotective effect of PACAP against kainic acid-induced neurotoxicity in rat retina.Ann. NY Acad. Sci. 1070, 531–534.
Shioda S, H Ozawa, K Dohi, H Mizushima, K Matsumoto, S Nakajo, A Takaki, CJ Zhou, Y Nakai and A Arimura (1998) PACAP protects hippocampal neurons against apoptosis: involvement of JNK/SAPK signaling pathway.Ann. NY Acad. Sci. 865, 111–117.
Shioda S, H Ohtaki, T Nakamachi, K Dohi, J Watanabe, S Nakajo, S Arata, S Kitamura, H Okuda, F Takenoya and Y Kitamura (2006) Pleiotropic functions of PACAP in the CNS. Neuroprotection and neurodevelopment.Ann. NY Acad. Sci. 1070, 550–560.
Shoge K, HK Mishima, T Saitoh, K Ishihara, Y Tamura, H Shiomi and M Sasa (1999) Attenuation by PACAP of glutamate-induced neurotoxicity in cultured retinal neurons.Brain Res. 839, 66–73.
Silveira MS, MR Costa, M Bozza and R Linden (2002) Pituitary adenylate cyclase activating polypeptide prevents induced cell death in retinal tissue through activation of cyclic AMP-dependent protein kinase.J. Biol. Chem. 277, 16075–16080.
Smythies J (1999) The neurotoxicity of glutamate, dopamine, iron and reactive oxygen species: functional interrelationships in health and disease: a review — discussion.Neurotox. Res. 1, 27–39.
Somogyvari-Vigh A and D Reglodi (2004) Pituitary adenylate cyclase activating polypeptide: a potential neuroprotective peptide. Review.Curr. Pharm. Des. 10, 2861–2889.
Sucher NJ, SA Lipton and EB Dreyer (1997) Molecular basis of glutamate toxicity in retinal ganglion cells.Vision Res. 37, 3483–3493.
Tamas A, R Gabriel, B Racz, V Denes, P Kiss, A Lubics, I Lengvari and D Reglodi (2004) Effects of pituitary adenylate cyclase activating polypeptide in retinal degeneration induced by monosodium-glutamate.Neurosci. Lett. 372, 110–113.
Vaudry D, BJ Gonzalez, M Basille, L Yon, A Fournier and H Vaudry (2000) Pituitary adenylate cyclase activating polypeptide and its receptors: from structure to functions.Pharmacol. Rev. 52, 269–324.
Vaudry D, A Falluel-Morel, M Basille, TF Pamantung, M Fontaine, A Fournier, H Vaudry and BJ Gonzalez (2003) Pituitary adenylate cyclase activating polypeptide prevents C2-ceramide-induced apoptosis of cerebellar granule cells.J. Neurosci. Res. 72, 303–316.
Vereczki V, K Koves, A Csaki, K Grosz, GE Hoffman and G Fiskum (2006) Distribution of hypothalamic, hippocampal and other limbic peptidergic neuronal cell bodies giving rise to retinopetal fibers: anterograde and retrograde tracing and neuropeptide immunohistochemical studies.Neuroscience 140, 1089–1190.
Vidal-Sanz M, M Lafuente, P Sobrado-Calvo, I Selles-Navarro, E Rodriguez, S Mayor-Torroglosa and MP Villegas-Perez (2000) Death and neuroprotection of retinal ganglion cells after different types of injury.Neurotox. Res. 2, 215–227.
Wang HG, N Pathan, IM Ethell, S Krajewski, Y Yamaguci, F Shibasaki, F McKeon, T Bobo, TF Franke and JC Reed (1999) Ca2+-induced apoptosis through calcineurin dephosphorylation of Bad.Science 284, 339–343.
Wang X, YK Ng and SS Tay (2005) Factors contributing to neuronal degeneration in retinas of experimental glaucomatous rats.J. Neurosci. Res. 82, 674–689.
Waschek JA (2002) Multiple actions of pituitary adenylyl cyclase activating peptide in nervous system development and regeneration.Dev. Neurosci. 24, 14–23.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rácz, B., Gallyas, F., Kiss, P. et al. 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. neurotox res 12, 95–104 (2007). https://doi.org/10.1007/BF03033918
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF03033918