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Effects of PACAP on the Circadian Changes of Signaling Pathways in Chicken Pinealocytes

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Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in the regulation of circadian rhythms. In mammals, the brain’s biological clock is the suprachiasmatic nucleus, receiving photic information from the retina through the retinohypothalamic pathway, where PACAP is the main cotransmitter of glutamate. The primary conductor of circadian rhythms of birds is the pineal gland. The presence of PACAP has been demonstrated both in the rat and avian pineal gland, where PACAP stimulates melatonin synthesis. The signaling mechanism, by which PACAP modulates melatonin synthesis and circadian rhythmic functions of the pineal gland, is only partially known. The aim of the present study was to investigate the effects of PACAP on the changes of p38 mitogen-activated protein kinase (MAPK) and 14-3-3 protein in chick pineal cell culture both of which have been shown to participate in the regulation of rhythmic functions. Pineal cells were treated with 1, 10, or 100 nM PACAP38 every 4 h during a 24-h period. The phosphorylation of p38 MAPK showed obvious changes during the observed 24 h, while the level of 14-3-3 protein did not. We found that the lowest used dose of PACAP did not cause any phase alteration in p38 MAPK phosphorylation. Ten nM PACAP induced a 4-h-long delay and 100 nM abolished the circadian changes of p38 MAPK phosphorylation. PACAP was not effective on the level of 14-3-3 protein in the early morning hours, and only the highest tested dose (100 nM) could evoke a change in the appearance of 14-3-3 between midday and midnight hours. In summary, PACAP modulated the phosphorylation of p38 MAPK and the appearance of 14-3-3 protein in the chicken pineal cells, but these effects were dose dependent and also depended on the time of day.

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References

  • Antle, M. C., Kriegsfeld, L. J., & Silver, R. (2005). Signaling within the master clock of the brain: Localized activation of mitogen-activated protein kinase by gastrin-releasing peptide. Journal of Neuroscience, 25, 2447–2454.

    Article  PubMed  CAS  Google Scholar 

  • Arimura, A. (2007). PACAP: The road to discovery. Peptides, 28, 1617–1619.

    Article  PubMed  CAS  Google Scholar 

  • Botia, B., Basille, M., Allais, A., et al. (2007). Neurotrophic effects of PACAP in the cerebellar cortex. Peptides, 28, 1746–1752.

    Article  PubMed  CAS  Google Scholar 

  • Braas, K. M., Schutz, K. C., Bond, J. P., Vizzard, M. A., Girard, B. M., & May, V. (2007). Microarray analyses of pituitary adenylate cyclase activating polypeptide (PACAP)-regulated gene targets in sympathetic neurons. Peptides, 28, 1856–1870.

    Article  PubMed  CAS  Google Scholar 

  • Chen, D., Buchanan, J. M., Ding, J., Hannibal, J., & Gillette, M. U. (1999). Pituitary adenylate cyclase activating peptide: A pivotal modulator of glutamatergic regulation of the suprachiasmatic circadian clock. Proceedings of the National Academy of Sciences, 96, 13468–13473.

    Article  CAS  Google Scholar 

  • Chik, C. L., Mackova, M., Price, D., & Ho, A. K. (2004). Adrenergic regulation and diurnal rhythm of p38 mitogen-activated protein kinase phosphorylation in the rat pineal gland. Endocrinology, 145, 5194–5201.

    Article  PubMed  CAS  Google Scholar 

  • Colwell, C. S., Michel, S., Itri, J., et al. (2004). Selective deficits in the circadian light response in mice lacking PACAP. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 287, 1194–1201.

    Google Scholar 

  • Coogan, A. N., & Piggins, H. D. (2004). MAP kinases in the mammalian circadian system—key regulators of the clock function. Journal of Neurochemistry, 90, 769–775.

    Article  PubMed  CAS  Google Scholar 

  • Csernus, V. J. (2006). The avian pineal gland. Chronobiology International, 23, 329–339.

    Article  PubMed  CAS  Google Scholar 

  • Csernus, V., Jozsa, R., Reglodi, D., et al. (2004). The effect of PACAP on rhythmic melatonin release of avian pineals. General and Comparative Endocrinology, 135, 62–69.

    Article  PubMed  CAS  Google Scholar 

  • Dziema, H., & Obrietan, K. (2002). PACAP potentiates L-type calcium channel conductance in suprachiasmatic nucleus neurons by activating the MAPK pathways. Journal of Neurophysiology, 88, 1374–1386.

    PubMed  CAS  Google Scholar 

  • Dziema, H., Oatis, B., Butcher, G. Q., et al. (2003). The ERK/MAP kinase pathway couples light to immediate-early gene expression in the suprachiasmatic nucleus. European Journal of Neuroscience, 17, 1617–1627.

    Article  PubMed  Google Scholar 

  • Fahrenkrug, J. (2006). PACAP-a multifaceted neuropeptide. Chronobiology International, 23, 53–61.

    Article  PubMed  CAS  Google Scholar 

  • Faluhelyi, N., Reglodi, D., Lengvári, I., & Csernus, V. (2004). Development of the circadian melatonin rhythm and the effect of PACAP on melatonin release in the embryonic chicken pineal gland. An in vitro study. Regulatory Peptides, 123, 23–28.

    Article  PubMed  CAS  Google Scholar 

  • Faluhelyi, N., Reglodi, D., & Csernus, V. (2006). The effects of PACAP and VIP on the in vitro melatonin secretion from the embryonic chicken pineal gland. Annals of the New York Academy of Sciences, 1070, 271–275.

    Article  PubMed  CAS  Google Scholar 

  • Fujii, H., Ishihama, T., Ago, Y., et al. (2007). Methamphetamine-induced hyperactivity and behavioral sensitization in PACAP deficient mice. Peptides, 28, 1674–1679.

    Article  PubMed  CAS  Google Scholar 

  • Gray, S. L., Yamaguchi, N., Vencova, P., & Sherwood, N. M. (2002). Temperature-sensitive phenotype in mice lacking pituitary adenylate cyclase-activating polypeptide. Endocrinology, 143, 3946–3954.

    Article  PubMed  CAS  Google Scholar 

  • Hannibal, J. (2002). Neurotransmitters of the retino-hypothalamic tract. Cell Tissue Research, 309, 73–88.

    Article  PubMed  CAS  Google Scholar 

  • Hannibal, J., & Fahrenkrug, J. (2004). Melanopsin containing retinal ganglion cells are light responsive from birth. Neuroreport, 15, 2317–2320.

    Article  PubMed  CAS  Google Scholar 

  • Hannibal, J., Ding, J. M., Chen, D., et al. (1997). Pituitary adenylate cyclase activating peptide (PACAP) in the retinohypothalamic tract: A potential daytime regulator of the biological clock. Journal of Neuroscience, 17, 2637–2644.

    PubMed  CAS  Google Scholar 

  • Hannibal, J., Møller, M., Ottersen, O. P., & Fahrenkrug, J. (2000). PACAP and glutamate are co-stored in the retinohypothalamic tract. Journal of Comparative Neurology, 418, 147–155.

    Article  PubMed  CAS  Google Scholar 

  • Hannibal, J., Jamen, F., Nielsen, H. S., Journot, L., Brabet, P., & Fahrenkrug, J. (2001). Dissociation between light-induced phase shift of the circadian rhythm and clock gene expression in mice lacking the pituitary adenylate cyclase activating polypeptide type 1 receptor. Journal of Neuroscience, 21, 4883–4890.

    PubMed  CAS  Google Scholar 

  • Hannibal, J., Hindersson, P., Nevo, E., & Fahrenkrug, J. (2002). The circadian photopigment melanopsin is expressed in the blind subterranean mole rat, Spalax. Neuroreport, 13, 1411–1414.

    Article  PubMed  CAS  Google Scholar 

  • Harrington, M. E., Hoque, S., Hall, A., Golombek, D., & Biello, S. (1999). Pituitary adenylate cyclase activating peptide phase shifts circadian rhythms in a manner similar to light. Journal of Neuroscience, 19, 6637–6642.

    PubMed  CAS  Google Scholar 

  • Hayashi, Y., Sanada, K., Hirota, T., Shimizu, F., & Fukada, Y. (2003). p38 mitogen-activated protein kinase regulates oscillation of chick pineal circadian clock. Journal of Biological Chemistry, 278, 25166–25171.

    Article  PubMed  CAS  Google Scholar 

  • Helyes, Z., Pozsgai, G., Borzsei, R., et al. (2007). Inhibitory effect of PACAP-38 on acute neurogenic and non-neurogenic inflammatory processes in the rat. Peptides, 28, 1847–1855.

    Article  PubMed  CAS  Google Scholar 

  • Kawaguchi, C., Tanaka, K., Isojima, Y., et al. (2003). Changes in light-induced phase shift of circadian rhythm in mice lacking PACAP. Biochemical and Biophysical Research Communications, 310, 169–175.

    Article  PubMed  CAS  Google Scholar 

  • Kiss, P., Reglodi, D., Tamas, A., et al. (2007). Changes of PACAP levels in the brain show gender differences following short-term water and food deprivation. General and Comparative Endocrinology, 152, 225–230.

    Article  PubMed  CAS  Google Scholar 

  • Laburthe, M., Couvineau, A., & Tan, V. (2007). Class II G-protein-coupled receptors for VIP and PACAP: Structure, models of activation and pharmacology. Peptides, 28, 1631–1639.

    Article  PubMed  CAS  Google Scholar 

  • Matsuda, K., & Maruyama, K. (2007). Regulation of feeding behavior by pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) in vertebrates. Peptides, 28, 1761–1766.

    Article  PubMed  CAS  Google Scholar 

  • Matsuno, R., Ohtaki, H., Nakamachi, T., et al. (2008). Distribution and localization of pituitary adenylate cyclase-activating polypeptide-specific receptor (PAC1R) in the rostral migratory stream of the infant mouse brain. Regulatory Peptides, 145, 80–87.

    Article  PubMed  CAS  Google Scholar 

  • Minami, Y., Furuno, K., Akiyama, M., Moriya, T., & Shibata, S. (2002). Pituitary adenylate cyclase activating polypeptide produces a phase shift associated with induction of mPer expression in the mouse suprachiasmatic nucleus. Neuroscience, 113, 37–45.

    Article  PubMed  CAS  Google Scholar 

  • Miyata, A., Arimura, A., Dahl, R. R., et al. (1989). Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochemical and Biophysical Research Communications, 164, 567–574.

    Article  PubMed  CAS  Google Scholar 

  • Moller, M., Fahrenkrug, J., & Hannibal, J. (1999). Innervation of the rat pineal gland by pituitary adenylate cyclase-activating polypeptide (PACAP)-immunoreactive nerve fibres. Cell Tissue Research, 296, 247–257.

    Article  PubMed  CAS  Google Scholar 

  • Nagy, A. D., & Csernus, V. J. (2007). The role of PACAP in the control of circadian expression of clock genes in the chicken pineal gland. Peptides, 28, 1767–1774.

    Article  PubMed  CAS  Google Scholar 

  • Nakahara, K., Abe, Y., Murakami, T., Shiota, K., & Murakami, N. (2002). Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in melatonin release via the specific receptor PACAP-r1, but not in the circadian oscillator, in chick pineal cell. Brain Research, 939, 19–25.

    Article  PubMed  CAS  Google Scholar 

  • Nielsen, H. S., Hannibal, J., Knudsen, S. M., & Fahrenkrug, J. (2001). Pituitary adenylate cyclase activating polypeptide induces period1 and period2 gene expression in the rat suprachiasmatic nucleus during late night. Neuroscience, 103, 433–441.

    Article  PubMed  CAS  Google Scholar 

  • Piggins, H. D., Marchant, E. G., Goguen, D., & Rusak, B. (2001). Phase-shifting effects of pituitary adenylate cyclase activating polypeptide on hamster wheel-running rhythms. Neuroscience Letters, 305, 25–28.

    Article  PubMed  CAS  Google Scholar 

  • Pizzio, G. A., Hainich, E. C., Ferreyra, G. A., Coso, O. A., & Golombek, D. A. (2003). Circadian and photic regulation of ERK, JNK and p38 in the hamster SCN. Neuroreport, 14, 1417–1419.

    Article  PubMed  CAS  Google Scholar 

  • Pizzio, G. A., Hainich, E. C., Plano, S. A., Ralph, M. R., & Golombek, D. A. (2005). Nerve growth factor-induced circadian phase shifts and MAP kinase activation in the hamster suprachiasmatic nuclei. European Journal of Neuroscience, 22, 665–671.

    Article  PubMed  Google Scholar 

  • Racz, B., Gallyas Jr., F., Kiss, P., et al. (2006). The neuroprotective effects of PACAP in monosodium glutamate-induced retinal lesion involves inhibition of proapoptotic signaling pathways. Regulatory Peptides, 137, 20–26.

    Article  PubMed  CAS  Google Scholar 

  • Racz, B., Gasz, B., Gallyas Jr., F., et al. (2007a). 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. Regulatory Peptides, 145, 105–115.

    Article  PubMed  CAS  Google Scholar 

  • Racz, B., Gasz, B., Gallyas Jr., F., et al. (2007b). Effects of pituitary adenylate cyclase activating polypeptide (PACAP) on the PKA–Bad–14-3-3 signaling pathways in the protective glutamate-induced retinal injury in neonatal rats. Neurotoxicity Research, 12, 95–104.

    Article  PubMed  CAS  Google Scholar 

  • Ravni, A., Bourgault, S., Lebon, A., et al. (2006). The neurotrophic effects of PACAP in PC12 cells: Control by multiple transduction pathways. Journal of Neurochemistry, 98, 321–329.

    Article  PubMed  CAS  Google Scholar 

  • Rekasi, Z., & Czompoly, T. (2002). Accumulation of rat pineal serotonin N-acetyltransferase mRNA induced by pituitary adenylate cyclase activating polypeptide and vasoactive intestinal peptide in vitro. Journal of Molecular Endocrinology, 28, 19–31.

    Article  PubMed  CAS  Google Scholar 

  • Rosiak, J., & Zawilska, J. B. (2006). 14-3-3 proteins—a role in the regulation of melatonin biosynthesis. Postepy Biochemii, 52, 35–41.

    PubMed  CAS  Google Scholar 

  • Samal, B., Gerdin, M. J., Huddleston, D., et al. (2007). Meta-analysis of microarray-derived data from PACAP-deficient adrenal gland in vivo and PACAP-treated chromaffin cells identifies distinct classes of PACAP-regulated genes. Peptides, 28, 1871–1882.

    Article  PubMed  CAS  Google Scholar 

  • Sherwood, N. M., Krueckl, S. L., & McRory, J. E. (2000). The origin and function of the pituitary adenylate cyclase activating polypeptide (PACAP)/glucagon superfamily. Endocrine Reviews, 21, 619–670.

    Article  PubMed  CAS  Google Scholar 

  • Sherwood, N. M., Adams, B. A., Isaac, E. R., Wu, S., & Fradinger, E. A. (2007). Knocked down and out: PACAP in development, reproduction and feeding. Peptides, 28, 1680–1687.

    Article  PubMed  CAS  Google Scholar 

  • Shioda, S., Ohtaki, H., Nakamachi, T., et al. (2006). Pleiotropic functions of PACAP in the CNS. Neuroprotection and neurodevelopment. Annals of the New York Academy of Sciences, 1070, 550–560.

    Article  PubMed  CAS  Google Scholar 

  • Simonneaux, V., Ouichou, P., & Pevet, P. (1993). Pituitary adenylate cyclase activating polypeptide (PACAP) stimulates melatonin synthesis from rat pineal gland. Brain Research, 603, 148–152.

    Article  PubMed  CAS  Google Scholar 

  • Somogyvari-Vigh, A., & Reglodi, D. (2004). Pituitary adenylate cyclase activating polypeptide: A potential neuroprotective peptide. Current Pharmaceutical Design, 10, 2861–2889.

    Article  PubMed  CAS  Google Scholar 

  • Stumm, R., Kolodziej, A., Prinz, V., Endres, M., Wu, D. F., & Hollt, V. (2007). Pituitary adenylate cyclase-activating polypeptide is up-regulated in cortical pyramidal cells after focal ischemia and protects neurons from mild hypoxic/ischemic damage. Journal of Neurochemistry, 103, 1666–1681.

    Article  PubMed  CAS  Google Scholar 

  • Vaudry, D., Gonzalez, B. J., Basille, M., Yon, L., Fournier, A., & Vaudry, H. (2000). Pituitary adenylate cyclase activating polypeptide and its receptors: From structure to functions. Pharmacological Reviews, 52, 269–324.

    PubMed  CAS  Google Scholar 

  • Waschek, J. A. (2002). Multiple actions of pituitary adenylyl cyclase activating peptide in nervous system development and regeneration. Developmental Neuroscience, 24, 14–23.

    Article  PubMed  CAS  Google Scholar 

  • Yadav, G., Straume, M., Heath 3rd, J., & Zatz, M. (2003). Are changes in MAPK/ERK necessary or sufficient for entrainment in chick pineal cells? Journal of Neuroscience, 23, 10021–10031.

    PubMed  CAS  Google Scholar 

  • Zhou, C. J., Shioda, S., Yada, T., Inagaki, N., Pleasure, S. J., & Kikuyama, S. (2002). PACAP and its receptors exert pleiotropic effects in the nervous system by activating multiple signaling pathways. Current Protein and Peptide Science, 3, 423–439.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Hungarian Science Research Fund (OTKA T046589, T046256, F 67830, K72592, and F048908), Bolyai Scholarship, and ETT439/2006.

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Authors and Affiliations

  1. Department of Surgical Research and Techniques, Medical Faculty, University of Pecs, Kodaly Z. u. 20, 7624, Pecs, Hungary

    Boglarka Racz

  2. Department of Anatomy, University of Pecs, Pecs, Hungary

    Gabriella Horvath, Nandor Faluhelyi, Andras D. Nagy, Andrea Tamas, Peter Kiss, Balazs Gaszner, Valer Csernus & Dora Reglodi

  3. Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary

    Ferenc Gallyas Jr

  4. Department of Medical Chemistry, University of Szeged, Szeged, Hungary

    Gabor Toth

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  1. Boglarka Racz
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  2. Gabriella Horvath
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  3. Nandor Faluhelyi
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  4. Andras D. Nagy
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  5. Andrea Tamas
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  6. Peter Kiss
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  10. Valer Csernus
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Correspondence to Boglarka Racz.

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Racz, B., Horvath, G., Faluhelyi, N. et al. Effects of PACAP on the Circadian Changes of Signaling Pathways in Chicken Pinealocytes. J Mol Neurosci 36, 220–226 (2008). https://doi.org/10.1007/s12031-008-9112-4

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