Skip to main content
SpringerLink
Log in

Involvement of β Isoform of PKC in PACAP-induced Differentiation of Neural Stem Cells into Astrocytes

  • Conference paper
New Frontiers in Regenerative Medicine

  • 435 Accesses

Abstract

We have found that pituitary adenylate cyclase-activating polypeptide (PACAP) induces the differentiation of mouse neural stem cells (NSCs) into astrocytes via a mechanism that is independent of the cyclic AMP/protein kinase A pathway. NSCs expressed PACAP receptor, PAC1 on the plasma membranes. PACAP-induced differentiation was inhibited by the most potent antagosist, the phospholipase C (PLC) inhibitor, the protein kinase C (PKC) inhibitor, and the intracellular calcium chelator, and was mimicked by phorbol ester (PMA). These results suggest that the PACAP-generated signal was mediated via the PACAP receptor, PAC1 stimulated heterotrimeric G-protein, resulting in activation of PLC, followed by conventional PKC (cPKC). Embryonic NSCs expressed α, βI and βII isoforms of cPKC, but lacked PKCγ. When NSCs were exposed to PACAP, protein expression levels of the βI and βII transiently increased prior to differentiation, returning to basal levels by day 4, whereas the level of PKCα increased linearly up to day 6. Overexpression of PKCβII synergistically enhanced differentiation in the presence of PACAP, whereas expression of the dominant-negative mutant of PKCβII proved inhibitory. These results indicate that the βI/βII isoforms of PKC play a crucial role in the PACAP-induced differentiation of mouse embryonic NSCs into astrocytes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Alexander SPH, Peters JA (Eds.) (2000) TiPS Receptor and Ion Channel Nomenclature Supplement. Elsevier.

    Google Scholar 

  • Al-Maghtheh M, Vithana EN, Inglehearn CF, Moore T, Bird AC, Bhattacharya SS, (2001) A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19ql3.4 (RPll). Mol Cell 8:375–381

    Article  PubMed  Google Scholar 

  • Anderson DJ (2001) Stem cells and pattern formation in the nervous system: the possible versus the actual. Neuron 30:19–35

    Article  PubMed  CAS  Google Scholar 

  • Arimura A, Somogyvari-Vigh A, Miyata A, Mizuno K, Coy DH, Kitada C (1991) Tissue distribution of PACAP as determined by RIA: highly abundant in the rat brain and testes. Endocrinology 129:2787–2789

    Article  PubMed  CAS  Google Scholar 

  • Arimura A, Shioda S (1995) Pituitary adenylate cyclase activating polypeptide (PACAP) and its receptors: neuroendocrine and endocrine interaction. Front. Neuroendocrinol 16:53–88

    Article  PubMed  CAS  Google Scholar 

  • Arimura A (1998) Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems. Jpn J Physiol 48:301–331

    Article  PubMed  CAS  Google Scholar 

  • Berkner KL, (1992) Expression of heterologous sequences in adenoviral vectors. Curr Top Microbiol Immunol 158:39–66

    PubMed  CAS  Google Scholar 

  • Berridge MJ (1987) Inositol trisphosphate and diacylglycerol: two interacting second messengers. Annu Rev Biochem 56:159–193

    PubMed  CAS  Google Scholar 

  • Campbell JM, Payne AP, Gilmore DP, Russell D, McGadey J, Clarke DJ, Branton R, Davies RW, Sutcliffe RG (1997) Age changes in dopamine levels in the corpus striatum of Albino Swiss (AS) and AS/AGU mutant rats. Neurosci Lett 12:54–56

    Article  Google Scholar 

  • Campbell JM, Gilmore DP, Russell D, Growney CA, Favor G, Kennedy AK, Davies RW, Payne AP, Stone TW (2000) Pharmacological analysis of extracellular dopamine and metabolites in the striatum of conscious as/agu rats, mutants with locomotor disorder. Neuroscience 100:45–52

    Article  PubMed  CAS  Google Scholar 

  • Chatterjee TK, Sharma RV, Fisher RA (1996) Molecular cloning of a novel variant of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor that stimulates calcium influx by activation of L-type calcium channels. J Biol Chem 271:32226–32232

    Article  PubMed  CAS  Google Scholar 

  • Chen DH, Brkanac Z, Verlinde CL, Tan XJ, Bylenok L, Nochlin D, Matsushita M, Lipe H, Wolff J, Fernandez M, Cimino PJ, Bird TD, Raskind WH (2003) Missense mutations in the regulatory domain of PKC y: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet 72:839–849

    Article  PubMed  CAS  Google Scholar 

  • Gage FH, Ray J, Fisher LJ (1995) Isolation, characterization, and use of stem cells from the CNS. Annu Rev Neurosci 18:159–192

    Article  PubMed  CAS  Google Scholar 

  • Gage FH (2000) Mammalian neural stem cells. Science 287:1433–1438

    Article  PubMed  CAS  Google Scholar 

  • Garnica AD, Chan WY (1996) The role of the placenta in fetal nutrition and growth. J Am Coll Nutr 15:206–222

    PubMed  CAS  Google Scholar 

  • Hansel DE, May V, Eipper BA, Ronnett GV (2001) Pituitary adenylyl cyclase-activating peptides and alpha-amidation in olfactory neurogenesis and neuronal survival in vitro. J Neurosci 21:4625–4636

    PubMed  CAS  Google Scholar 

  • Herbert JM, Augereau JM, Maffrand J.P (1990) Chelerythrine is a potent and specific inhibitor of protein kinase C. Biochem Biophys Res Commun 172:993–999.

    Article  PubMed  CAS  Google Scholar 

  • Hill JM, Lee SJ, Dibbern DA Jr, Fridkin M, Gozes I, Brenneman DE (1999) Pharmacologically distinct vasoactive intestinal peptide binding sites: CNS localization and role in embryonic growth. Neuroscience 93:783–791

    Article  PubMed  CAS  Google Scholar 

  • Hubbard KB, Hepler JR (2006) Cell signaling diversity of the Gqot family of heterotrimeric G proteins. Cell Signal 18:135–150

    Article  PubMed  CAS  Google Scholar 

  • Irie K, Nakahara A, Nakagawa Y, Ohigashi H, Shindo M, Fukuda H, Konishi H, Kikkawa U, Kashiwagi K, Saito N (2002) Establishment of a binding assay for protein kinase C isozymes using synthetic C1 peptides and development of new medicinal leads with protein kinase C isozyme and C1 domain selectivity. Pharmacol Ther 93:271–281

    Article  PubMed  CAS  Google Scholar 

  • Johe KK, Hazel TG, Muller T, Dugich-Djordjevic MM, McKay RD (1996) Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev 10:3129–3140

    PubMed  CAS  Google Scholar 

  • Kikkawa U, Kishimoto A, Nishizuka Y (1989) The protein kinase C family: heterogeneity and its implications. Annu Rev Biochem 58:31–44

    Article  PubMed  CAS  Google Scholar 

  • Kiley SC, Jaken S (1990) Activation of alpha-protein kinase C leads to association with detergent-insoluble components of GH4C1 cells. Mol Endocrinol 4:59–68

    Article  PubMed  CAS  Google Scholar 

  • Kraft AS, Anderson WB, Cooper HL, Sando JJ (1982) Decrease in cytosolic calcium/phospholipid-dependent protein kinase activity following phorbol ester treatment of EL4 thymoma cells. J Biol Chem 257:13193–13196

    PubMed  CAS  Google Scholar 

  • Kuhn HG, Svendsen CN (1999) Origins, functions, and potential of adult neural stem cells. Bioessays 21:625–630

    Article  PubMed  CAS  Google Scholar 

  • Lai C, Feng L (2004) Neuregulin induces proliferation of neural progenitor cells via PLC/PKC pathway. Biochem Biophys Res Commun 319:603–611

    Article  PubMed  CAS  Google Scholar 

  • Lendahl U, Zimmerman LB, McKay RD (1990) CNS stem cells express a new class of intermediate filament protein. Cell 60:585–595

    Article  PubMed  CAS  Google Scholar 

  • Love JA, Szebeni K (1999) Morphology and histochemistry of the rabbit pancreatic innervation. Pancreas 18:53–64

    Article  PubMed  CAS  Google Scholar 

  • Lu N, DiCicco-Bloom E (1997) Pituitary adenylate cyclase-activating polypeptide is an autocrine inhibitor of mitosis in cultured cortical precursor cells. Proc Natl Acad Sci USA 94:3357–3362

    Article  PubMed  CAS  Google Scholar 

  • Luts L, Sundler F (1994) Peptide-containing nerve fibers in the parathyroid glands of different species. Regul Pept 50: 147–158

    Article  PubMed  CAS  Google Scholar 

  • Mercer A, Rönnholm H, Holmberg J, Lundh H, Heidrich J, Zachrisson O, Ossoinak A, Frisèn J, Patrone C (2004) PACAP promotes neural stem cell proliferation in adult mouse brain. J Neurosci Res 76:205–215

    Article  PubMed  CAS  Google Scholar 

  • Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, Culler MD, Coy DH (1989) Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 164:567–574

    Article  PubMed  CAS  Google Scholar 

  • Mochly-Rosen D, Henrich CJ, Cheever L, Khaner H, Simpson PC (1990) Cell Regul 1:693–706

    PubMed  CAS  Google Scholar 

  • Nicot A, Dicicco-Bloom EM (2001) Regulation of neuroblast mitosis is determined by PACAP receptor isoform expression. Proc Natl Acad Sci USA 98:4758–4763

    Article  PubMed  CAS  Google Scholar 

  • Nishizuka Y (1988) The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 334:661–665

    Article  PubMed  CAS  Google Scholar 

  • Nishizuka Y. (1992) Intracellular signalling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607–614

    Article  PubMed  CAS  Google Scholar 

  • Nishizuka Y. (1995) Protein kinase C and lipid signaling for sustained cellular responses. FASEB J 9:484–496

    PubMed  CAS  Google Scholar 

  • Ohba M, Ishino K, Kashiwagi M, Kawabe S, Chida K, Huh NH, Kuroki T (1998) Induction of differentiation in normal human keratinocytes by adenovirus-mediated introduction of the eta and delta isoforms of protein kinase C. Mol Cell Biol 18:5199–5207

    PubMed  CAS  Google Scholar 

  • Ohno F, Watanabe J, Sekihara H, Hirabayashi T, Arata S, Kikuyama S, Shioda S, Nakaya K, Nakajo S (2005) Pituitary adenylatecyclase-activating polypeptide promotes differentiation of mouse neural stem cells into astrocytes. Regul. Peptides 126:115–122

    Article  CAS  Google Scholar 

  • Ohno S, Kawasaki H, Imajoh S, Suzuki K, Inagaki M, Yokokura H, Sakoh T, Hidaka H (1987) Tissue-specific expression of three distinct types of rabbit protein kinase C. Nature 325:161–166

    Article  PubMed  CAS  Google Scholar 

  • Oka M, Hitomi T, Okada T, Nakamura S, Nagai H, Ohba M, Kuroki T, Kikkawa U, Ichihashi M (2002) Dual regulation of phospholipase Dl by proteininase C α in vivo. Biochem Biophys Res Commun 294:1109–1113

    Article  PubMed  CAS  Google Scholar 

  • Ono Y, Fujii T, Igarashi K, Kuno T, Tanaka C, Kikkawa U, Nishizuka Y (1989) Phorbol ester binding to protein kinase C requires a cysteine-rich zinc-finger-like sequence. Proc Natl Acad Sci USA 86:4868–4871

    Article  PubMed  CAS  Google Scholar 

  • Payne AP, Campbell JM, Russell D, Favor G, Sutcliffe RG, Bennett NK, Davies RW, Stone TW (2000) The AS/AGU rat: a spontaneous model of disruption and degeneration in the nigrostriatal dopaminergic system. J Anat 196:629–33

    Article  PubMed  CAS  Google Scholar 

  • Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710

    Article  PubMed  CAS  Google Scholar 

  • Rhee SG (2001) Regulation of phosphoinositide-specific phospholipase C. Annu Rev Biochem 70:281–312

    Article  PubMed  CAS  Google Scholar 

  • Saito N, Kikkawa U, Nishizuka Y, Tanaka C (1988) Distribution of protein kinase C-like immunoreactive neurons in rat brain. J Neurosci 8:369–382

    PubMed  CAS  Google Scholar 

  • Saito N, Shirai Y (2002) Protein kinase Cγ (PKCγ): function of neuron specific isotype. J Biochem (Tokyo) 132:683–687

    CAS  Google Scholar 

  • Seki T, Adachi N, Ono Y, Mochizuki H, Hiramoto K, Amano T, Matsubayashi H, Matsumoto M, Kawakami H, Saito N, Sakai N (2005) Mutant protein kinase Cγ found in spinocerebellar ataxia type 14 is susceptible to aggregation and causes cell death. J Biol Chem 280:29096–29106

    Article  PubMed  CAS  Google Scholar 

  • Shioda S, Legradi G, Leung WC, Nakajo S, Nakaya K, Arimura A (1994) Localization of pituitary adenylate cyclase-activating polypeptide and its messenger ribonucleic acid in the rat testis by light and electron microscopic immunocytochemistry and in situ hybridization. Endocrinology 135:818–825

    Article  PubMed  CAS  Google Scholar 

  • Shioda S, Ohtaki H, Nakamachi T, Dohi K, Watanabe J, Nakajo S, Arata S, Kitamura S, Okuda H, Takenoya F, Kitamura Y (2006) Pleiotropic functions of PACAP in the CNS: Neuroprotection and Neurodevelopment. Ann NY Acad Sci in press

    Google Scholar 

  • Skoglosa Y, Takei N, Lindholm D (1999) Distribution of pituitary adenylate cyclase activating polypeptide mRNA in the developing rat brain. Brain Res Mol Brain Res 65:1–13

    Article  PubMed  CAS  Google Scholar 

  • Spengler D, Waeber C, Pantaloni C, Holsboer F, Bockaert J, Seeburg PH, Journot L (1993) Differential signal transduction by five splice variants of the PACAP receptor. Nature 365:170–175

    Article  PubMed  CAS  Google Scholar 

  • Stevanin G, Hahn V, Lohmann E, Bouslam N, Gouttard M, Soumphonphakdy C, Welter ML, Ollagnon-Roman E, Lemainque A, Ruberg M, Brice A, Durr A (2004) Mutation in the catalytic domain of protein kinase C γ and extension of the phenotype associated with spinocerebellar ataxia type 14. Arch Neurol 61:1242–1248

    Article  PubMed  Google Scholar 

  • Tastuno I, Somogyvari-Vigh A, Arimura A (1994) Developmental changes of pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor in the rat brain. Peptides 15:55–60

    Article  Google Scholar 

  • Vallejo I, Vallejo M (2002) Pituitary adenylate cyclase-activating polypeptide induces astrocyte differentiation of precursor cells from developing cerebral cortex. Mol Cell Neurosci 21:671–683

    Article  PubMed  CAS  Google Scholar 

  • Vaudry D, Gonzalez BJ, Basille M, Yon L, Fournier A, Vaudry H (2000) Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacol Rev 52:269–324

    PubMed  CAS  Google Scholar 

  • van de Warrenburg BP, Verbeek DS, Piersma SJ, Hennekam FA, Pearson PL, Knoers NV, Kremer HP, Sinke RJ (2003) Identification of a novel SCA14 mutation in a Dutch autosomal dominant cerebellar ataxia family. Neurology 61:1760–1765

    PubMed  Google Scholar 

  • Waschek JA, Casillas RA, Nguyen TB, DiCicco-Bloom EM, Carpenter EM, Rodriguez WI (1998) Neural tube expression of pituitary adenylate cyclase-activating peptide (PACAP) and receptor: potential role in patterning and neurogenesis. Proc Natl Acad Sci U S A 95:9602–9607

    Article  PubMed  CAS  Google Scholar 

  • Waschek JA, Ellison J, Bravo DT, Handley V (1996) Embryonic expression of vasoactive intestinal peptide (VIP) and VIP receptor genes. J Neurochem 66:1762–1765

    Article  PubMed  CAS  Google Scholar 

  • Watanabe J, Ohno F, Shioda S, Kikuyama S, Nakaya K, Nakajo S (2006a) Involvement of protein kinase C in the PACAP-induced differentiation of neural stem cells into astrocytes. Ann NY Acad Sci in press

    Google Scholar 

  • Watanabe J, Shioda S, Kikuyama S, Nakaya K, Nakajo S (2006b) Differentiation of neural stem cells into astrocytes by low concentration of pituitary adenylate cyclase-activating polypeptide (PACAP). Springer-Verlag Tokyo, in press.

    Google Scholar 

  • Weissman lL, Anderson DJ, Gage F (2001) Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu Rev CellDevBiol 17:387–403

    CAS  Google Scholar 

  • Yabe I, Sasaki H, Chen DH, Raskind WH, Bird TD, Yamashita I, Tsuji S, Kikuchi S, Tashiro K (2003) Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C γ. Arch Neurol 60:1749–1751

    Article  PubMed  Google Scholar 

  • Yoshida Y, Huang FL, Nakabayashi H, Huang K-P (1988) Tissue distribution of and developmental expression of protein kinase C isozymes. J Biol Chem 263:9868–9873

    PubMed  CAS  Google Scholar 

  • Zalewski PD, Forbes lJ, Valente L, Apostolou S, Hurst NP (1988) Translocation of protein kinase C to a Triton-insoluble sub-cellular compartment induced by the lipophilic gold compound auranofin. Biochem Pharmacol 37:1415–1417

    Article  PubMed  CAS  Google Scholar 

  • Zhou CJ, Shioda S, Shibanuma M, Nakajo S, Funahashi H, Nakai Y, Arimura A, Kikuyama S (1999) Pituitary adenylate cyclase-activating polypeptide receptors during development: expression in the rat embryo at primitive streak stage. Neuroscience 93:375–391

    Article  PubMed  CAS  Google Scholar 

  • Zhou CJ, Yada T, Kohno D, Kikuyama S, Suzuki R, Mizushima H, Shioda S (2001) PACAP activates PKA, PKC and Ca2+ signaling cascades in rat neuroepithelial cells. Peptides 22:1111–1117

    Article  PubMed  CAS  Google Scholar 

  • Zupan V, Hill JM, Brenneman DE, Gozes I, Fridkin M, Robberecht P, Evrard P, Gressens P (1998) Involvement of pituitary adenylate cyclase-activating polypeptide II vasoactive intestinal peptide 2 receptor in mouse neocortical astrocytogenesis. J Neurochem 70:2165–2173

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Shigeo Nakajo

    Present address: Laboratory of Biochemistry, Yokohama College of Pharmacy, 601 Matanocyo, Totsuka-ku, Yokohama, 245-0066, Japan

Authors and Affiliations

  1. Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Shigeo Nakajo & Fusako Ohno

  2. Department of First Anatomy, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Jun Watanabe & Seiji Shioda

  3. Department of Biology, School of Education, Waseda University, 1-6-1 Nishi-Waseda, Shinjuku-ku, Tokyo, 169-8050, Japan

    Jun Watanabe & Sakae Kikuyama

  4. Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Motoi Ohba

  5. Faculty of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, 956-8603, Japan

    Kazuyasu Nakaya

Authors
  1. Shigeo Nakajo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Motoi Ohba
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fusako Ohno
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sakae Kikuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuyasu Nakaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Seiji Shioda
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Showa University School of Medicine, 1-5-5 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Mitsuo Kusano MD, PhD (Professor of Surgery) & Seiji Shioda MD, PhD (Professor of Anatomy) (Professor of Surgery) &  (Professor of Anatomy)

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer

About this paper

Cite this paper

Nakajo, S. et al. (2007). Involvement of β Isoform of PKC in PACAP-induced Differentiation of Neural Stem Cells into Astrocytes. In: Kusano, M., Shioda, S. (eds) New Frontiers in Regenerative Medicine. Springer, Tokyo. https://doi.org/10.1007/978-4-431-38208-9_15

Download citation

  • DOI: https://doi.org/10.1007/978-4-431-38208-9_15

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-38207-2

  • Online ISBN: 978-4-431-38208-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation