Skip to main content
SpringerLink
Log in

Effects of PACAP on Biological Barriers

  • Chapter
  • First Online:
Pituitary Adenylate Cyclase Activating Polypeptide — PACAP

Part of the book series: Current Topics in Neurotoxicity ((Current Topics Neurotoxicity,volume 11))

Abstract

Biological barriers are formed by epithelial or specialized endothelial monolayers that separate and regulate the transport between compartments of different chemical compositions. The unique barrier properties of epithelial and brain endothelial cells (forming the blood–brain barrier) are primarily connected to the tight junctions that seal the intercellular way of transport. Here we review the functions of the different biological barriers, the regulation of tight junctions and the effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on epithelia and the cerebral endothelium. PACAP and PACAP receptors are widely expressed by these cells and also by immune cells, smooth muscle cells, and nerve endings associated to them. The protective effect of PACAP on kidney, lung, retinal pigment, and other epithelial cells in different pathological conditions is well documented; however, in brain endothelial cells no pro-survival effect of PACAP has been observed. Moreover, little is known about the effects of PACAP on tight junctions, except for the outer blood–retina barrier and the blood–brain barrier, where it helps to maintain the integrity of the barrier in pathological conditions.

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 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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

Abbreviations

BBB:

Blood–brain barrier

BRB:

Blood–retinal barrier

cAMP:

Cyclic adenosine monophosphate

CNS:

Central nervous system

EMT:

Epithelial–mesenchymal transition

MDCK:

Madin-Darby canine kidney

PKA:

Protein kinase A

RBEC:

Rat brain endothelial cell

RPE:

Retinal pigment epithelium

TJ:

Tight junction

ZO:

Zonula occludens

References

  1. Bauer HC, Traweger A, Zweimueller-Mayer J, Lehner C, Tempfer H, Krizbai I, et al. New aspects of the molecular constituents of tissue barriers. J Neural Transm. 2011;118:7–21.

    Article  CAS  PubMed  Google Scholar 

  2. Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, et al. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. 1993;123:1777–88.

    Article  CAS  PubMed  Google Scholar 

  3. Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S. Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol. 1998;141:1539–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kiuchi-Saishin Y, Gotoh S, Furuse M, Takasuga A, Tano Y, Tsukita S. Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. J Am Soc Nephrol. 2002;13:875–86.

    CAS  PubMed  Google Scholar 

  5. Traweger A, Toepfer S, Wagner RN, Zweimueller-Mayer J, Gehwolf R, Lehner C, et al. Beyond cell-cell adhesion: emerging roles of the tight junction scaffold ZO-2. Tissue Barriers. 2013;1:e25039.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Gonzalez-Mariscal L, Tapia R, Chamorro D. Crosstalk of tight junction components with signaling pathways. Biochim Biophys Acta. 1778;2008:729–56.

    Google Scholar 

  7. Krizbai IA, Deli MA. Signalling pathways regulating the tight junction permeability in the blood-brain barrier. Cell Mol Biol (Noisy-le-Grand). 2003;49:23–31.

    CAS  Google Scholar 

  8. Ishizaki T, Chiba H, Kojima T, Fujibe M, Soma T, Miyajima H, et al. Cyclic AMP induces phosphorylation of claudin-5 immunoprecipitates and expression of claudin-5 gene in blood-brain-barrier endothelial cells via protein kinase A-dependent and -independent pathways. Exp Cell Res. 2003;290:275–88.

    Article  CAS  PubMed  Google Scholar 

  9. Kis B, Deli MA, Kobayashi H, Abraham CS, Yanagita T, Kaiya H, et al. Adrenomedullin regulates blood-brain barrier functions in vitro. Neuroreport. 2001;12:4139–42.

    Article  CAS  PubMed  Google Scholar 

  10. Horai S, Nakagawa S, Tanaka K, Morofuji Y, Couraud PO, Deli MA, et al. Cilostazol strengthens barrier integrity in brain endothelial cells. Cell Mol Neurobiol. 2013;33:291–307.

    Article  CAS  PubMed  Google Scholar 

  11. Kohler K, Zahraoui A. Tight junction: a co-ordinator of cell signalling and membrane trafficking. Biol Cell. 2005;97:659–65.

    Article  PubMed  Google Scholar 

  12. Klingler C, Kniesel U, Bamforth SD, Wolburg H, Engelhardt B, Risau W. Disruption of epithelial tight junctions is prevented by cyclic nucleotide-dependent protein kinase inhibitors. Histochem Cell Biol. 2000;113:349–61.

    CAS  PubMed  Google Scholar 

  13. Sugawara T, Iwamoto N, Akashi M, Kojima T, Hisatsune J, Sugai M, et al. Tight junction dysfunction in the stratum granulosum leads to aberrant stratum corneum barrier function in claudin-1-deficient mice. J Dermatol Sci. 2013;70:12–8.

    Article  CAS  PubMed  Google Scholar 

  14. Suzuki T. Regulation of intestinal epithelial permeability by tight junctions. Cell Mol Life Sci. 2013;70:631–59.

    Article  CAS  PubMed  Google Scholar 

  15. Gunzel D, Yu AS. Claudins and the modulation of tight junction permeability. Physiol Rev. 2013;93:525–69.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7:41–53.

    Article  CAS  PubMed  Google Scholar 

  17. Wilhelm I, Krizbai IA. In vitro models of the blood-brain barrier for the study of drug delivery to the brain. Mol Pharm. 2014;11:1949–63.

    Article  CAS  PubMed  Google Scholar 

  18. Wilhelm I, Fazakas C, Krizbai IA. In vitro models of the blood-brain barrier. Acta Neurobiol Exp (Wars). 2011;71:113–28.

    Google Scholar 

  19. Owens MB, Hill AD, Hopkins AM. Ductal barriers in mammary epithelium. Tissue Barriers. 2013;1:e25933.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wilhelm I, Fazakas C, Tamas A, Toth G, Reglodi D, Krizbai IA. PACAP enhances barrier properties of cerebral microvessels. J Mol Neurosci. 2014;54:469–76.

    Article  CAS  PubMed  Google Scholar 

  21. Dogrukol-Ak D, Kumar VB, Ryerse JS, Farr SA, Verma S, Nonaka N, et al. Isolation of peptide transport system-6 from brain endothelial cells: therapeutic effects with antisense inhibition in Alzheimer and stroke models. J Cereb Blood Flow Metab. 2009;29:411–22.

    Article  CAS  PubMed  Google Scholar 

  22. Scuderi S, D’Amico AG, Castorina A, Imbesi R, Carnazza ML, D’Agata V. Ameliorative effect of PACAP and VIP against increased permeability in a model of outer blood retinal barrier dysfunction. Peptides. 2013;39:119–24.

    Article  CAS  PubMed  Google Scholar 

  23. Seki T, Shioda S, Ogino D, Nakai Y, Arimura A, Koide R. Distribution and ultrastructural localization of a receptor for pituitary adenylate cyclase activating polypeptide and its mRNA in the rat retina. Neurosci Lett. 1997;238:127–30.

    Article  CAS  PubMed  Google Scholar 

  24. Nilsson SF, De Neef P, Robberecht P, Christophe J. Characterization of ocular receptors for pituitary adenylate cyclase activating polypeptide (PACAP) and their coupling to adenylate cyclase. Exp Eye Res. 1994;58:459–67.

    Article  CAS  PubMed  Google Scholar 

  25. Chignard N, Mergey M, Barbu V, Finzi L, Tiret E, Paul A, et al. VPAC1 expression is regulated by FXR agonists in the human gallbladder epithelium. Hepatology. 2005;42:549–57.

    Article  CAS  PubMed  Google Scholar 

  26. Robberecht P, Gourlet P, Cauvin A, Buscail L, De Neef P, Arimura A, et al. PACAP and VIP receptors in rat liver membranes. Am J Physiol. 1991;260:G97–102.

    CAS  PubMed  Google Scholar 

  27. Liu S, Zeng Y, Li Y, Guo W, Liu J, Ouyang N. VPAC1 overexpression is associated with poor differentiation in colon cancer. Tumour Biol. 2014;35:6397–404.

    Article  CAS  PubMed  Google Scholar 

  28. Jonsson M, Norrgard O, Forsgren S. Epithelial expression of vasoactive intestinal peptide in ulcerative colitis: down-regulation in markedly inflamed colon. Dig Dis Sci. 2012;57:303–10.

    Article  PubMed  Google Scholar 

  29. Busto R, Carrero I, Guijarro LG, Solano RM, Zapatero J, Noguerales F, et al. Expression, pharmacological, and functional evidence for PACAP/VIP receptors in human lung. Am J Physiol. 1999;277:L42–8.

    CAS  PubMed  Google Scholar 

  30. Brubel R, Horvath G, Reglodi D, Lubics A, Tamas A, Kiss P, et al. Presence of pituitary adenylate cyclase activating polypeptide and its type I receptor in the rat kidney. Transplant Proc. 2011;43:1297–9.

    Article  CAS  PubMed  Google Scholar 

  31. Nagakawa O, Junicho A, Akashi T, Koizumi K, Matsuda T, Fuse H, et al. Vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide stimulate interleukin-6 production in prostate cancer cells and prostatic epithelial cells. Oncol Rep. 2005;13:1217–21.

    CAS  PubMed  Google Scholar 

  32. Garcia-Fernandez MO, Collado B, Bodega G, Cortes J, Ruiz-Villaespesa A, Carmena MJ, et al. Pituitary adenylate cyclase-activating peptide/vasoactive intestinal peptide receptors in human normal mammary gland and breast cancer tissue. Gynecol Endocrinol. 2005;20:327–33.

    Article  CAS  PubMed  Google Scholar 

  33. Steinhoff M, McGregor GP, Radleff-Schlimme A, Steinhoff A, Jarry H, Schmidt WE. Identification of pituitary adenylate cyclase activating polypeptide (PACAP) and PACAP type 1 receptor in human skin: expression of PACAP-38 is increased in patients with psoriasis. Regul Pept. 1999;80:49–55.

    Article  CAS  PubMed  Google Scholar 

  34. Helyes Z, Kun J, Dobrosi N, Sandor K, Nemeth J, Perkecz A, et al. Pituitary adenylate-cyclase activating polypeptide is up-regulated in murine skin inflammation and mediates transient receptor potential vanilloid-1-induced neurogenic edema. J Invest Dermatol. 2015;35:2209–18.

    Article  Google Scholar 

  35. Fischer TC, Dinh QT, Peiser C, Loser C, Fischer A, Groneberg DA. Simultaneous detection of receptor mRNA and ligand protein in human skin tissues. J Cutan Pathol. 2002;29:65–71.

    Article  PubMed  Google Scholar 

  36. Daniel PB, Kieffer TJ, Leech CA, Habener JF. Novel alternatively spliced exon in the extracellular ligand-binding domain of the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1R) selectively increases ligand affinity and alters signal transduction coupling during spermatogenesis. J Biol Chem. 2001;276:12938–44.

    Article  CAS  PubMed  Google Scholar 

  37. Scaldaferri ML, Modesti A, Palumbo C, Ulisse S, Fabbri A, Piccione E, et al. Pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP-receptor type 1 expression in rat and human placenta. Endocrinology. 2000;141:1158–67.

    CAS  PubMed  Google Scholar 

  38. Reubi JC, Laderach U, Waser B, Gebbers JO, Robberecht P, Laissue JA. Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin. Cancer Res. 2000;60:3105–12.

    CAS  PubMed  Google Scholar 

  39. Anderson CM, Mendoza ME, Kennedy DJ, Raldua D, Thwaites DT. Inhibition of intestinal dipeptide transport by the neuropeptide VIP is an anti-absorptive effect via the VPAC1 receptor in a human enterocyte-like cell line (Caco-2). Br J Pharmacol. 2003;138:564–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rosenberg GA. Neurological diseases in relation to the blood-brain barrier. J Cereb Blood Flow Metab. 2012;32:1139–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Forster C. Tight junctions and the modulation of barrier function in disease. Histochem Cell Biol. 2008;130:55–70.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Guttman JA, Finlay BB. Tight junctions as targets of infectious agents. Biochim Biophys Acta. 1788;2009:832–41.

    Google Scholar 

  43. Heimesaat MM, Dunay IR, Schulze S, Fischer A, Grundmann U, Alutis M, et al. Pituitary adenylate cyclase-activating polypeptide ameliorates experimental acute ileitis and extra-intestinal sequelae. PLoS One. 2014;9:e108389.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Kemeny A, Reglodi D, Cseharovszky R, Hashimoto H, Baba A, Szolcsanyi J, et al. Pituitary adenylate cyclase-activating polypeptide deficiency enhances oxazolone-induced allergic contact dermatitis in mice. J Mol Neurosci. 2010;42:443–9.

    Article  CAS  PubMed  Google Scholar 

  45. Elekes K, Sandor K, Moricz A, Kereskai L, Kemeny A, Szoke E, et al. Pituitary adenylate cyclase-activating polypeptide plays an anti-inflammatory role in endotoxin-induced airway inflammation: in vivo study with gene-deleted mice. Peptides. 2011;32:1439–46.

    Article  CAS  PubMed  Google Scholar 

  46. Abu-Hamdan MD, Drescher MJ, Ramakrishnan NA, Khan KM, Toma VS, Hatfield JS, et al. Pituitary adenylyl cyclase-activating polypeptide (PACAP) and its receptor (PAC1-R) in the cochlea: evidence for specific transcript expression of PAC1-R splice variants in rat microdissected cochlear subfractions. Neuroscience. 2006;140:147–61.

    Article  CAS  PubMed  Google Scholar 

  47. Li M, Khan AM, Maderdrut JL, Simon EE, Batuman V. The effect of PACAP38 on MyD88-mediated signal transduction in ischemia-/hypoxia-induced acute kidney injury. Am J Nephrol. 2010;32:522–32.

    Article  CAS  PubMed  Google Scholar 

  48. Li M, Balamuthusamy S, Khan AM, Maderdrut JL, Simon EE, Batuman V. Pituitary adenylate cyclase-activating polypeptide prevents cisplatin-induced renal failure. J Mol Neurosci. 2011;43:58–66.

    Article  CAS  PubMed  Google Scholar 

  49. Khan AM, Li M, Brant E, Maderdrut JL, Majid DS, Simon EE, et al. Renoprotection with pituitary adenylate cyclase-activating polypeptide in cyclosporine A-induced nephrotoxicity. J Investig Med. 2011;59:793–802.

    Article  CAS  PubMed  Google Scholar 

  50. Khan AM, Maderdrut JL, Li M, Toliver HL, Coy DH, Simon EE, et al. Pituitary adenylate cyclase-activating polypeptide prevents contrast-induced nephropathy in a novel mouse model. Physiol Rep. 2013;1:e00163.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Horvath G, Racz B, Szakaly P, Kiss P, Laszlo E, Hau L, et al. Mice deficient in neuropeptide PACAP demonstrate increased sensitivity to in vitro kidney hypoxia. Transplant Proc. 2010;42:2293–5.

    Article  CAS  PubMed  Google Scholar 

  52. Szakaly P, Laszlo E, Kovacs K, Racz B, Horvath G, Ferencz A, et al. Mice deficient in pituitary adenylate cyclase activating polypeptide (PACAP) show increased susceptibility to in vivo renal ischemia/reperfusion injury. Neuropeptides. 2011;45:113–21.

    Article  CAS  PubMed  Google Scholar 

  53. Reglodi D, Kiss P, Szabadfi K, Atlasz T, Gabriel R, Horvath G, et al. PACAP is an endogenous protective factor-insights from PACAP-deficient mice. J Mol Neurosci. 2012;48:482–92.

    Article  CAS  PubMed  Google Scholar 

  54. Yu R, Guo X, Huang L, Zeng Z, Zhang H. The novel peptide PACAP-TAT with enhanced traversing ability attenuates the severe lung injury induced by repeated smoke inhalation. Peptides. 2012;38:142–9.

    Article  CAS  PubMed  Google Scholar 

  55. Szanto Z, Sarszegi Z, Reglodi D, Nemeth J, Szabadfi K, Kiss P, et al. PACAP immunoreactivity in human malignant tumor samples and cardiac diseases. J Mol Neurosci. 2012;48:667–73.

    Article  CAS  PubMed  Google Scholar 

  56. Ferencz A, Kiss P, Weber G, Helyes Z, Shintani N, Baba A, et al. Comparison of intestinal warm ischemic injury in PACAP knockout and wild-type mice. J Mol Neurosci. 2010;42:435–42.

    Article  CAS  PubMed  Google Scholar 

  57. Ferencz A, Weber G, Helyes Z, Hashimoto H, Baba A, Reglodi D. Presence of endogenous PACAP-38 ameliorated intestinal cold preservation tissue injury. J Mol Neurosci. 2010;42:428–34.

    Article  CAS  PubMed  Google Scholar 

  58. Racz B, Horvath G, Reglodi D, Gasz B, Kiss P, Gallyas Jr F, et al. PACAP ameliorates oxidative stress in the chicken inner ear: an in vitro study. Regul Pept. 2010;160:91–8.

    Article  CAS  PubMed  Google Scholar 

  59. Nemeth A, Szabadfi K, Fulop B, Reglodi D, Kiss P, Farkas J, et al. Examination of calcium-binding protein expression in the inner ear of wild-type, heterozygous and homozygous pituitary adenylate cyclase-activating polypeptide (PACAP)-knockout mice in kanamycin-induced ototoxicity. Neurotox Res. 2014;25:57–67.

    Article  CAS  PubMed  Google Scholar 

  60. Kanekar S, Gandham M, Lucero MT. PACAP protects against TNFalpha-induced cell death in olfactory epithelium and olfactory placodal cell lines. Mol Cell Neurosci. 2010;45:345–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Atlasz T, Szabadfi K, Kiss P, Racz B, Gallyas F, Tamas A, et al. Pituitary adenylate cyclase activating polypeptide in the retina: focus on the retinoprotective effects. Ann N Y Acad Sci. 2010;1200:128–39.

    Article  CAS  PubMed  Google Scholar 

  62. Fabian E, Reglodi D, Mester L, Szabo A, Szabadfi K, Tamas A, et al. Effects of PACAP on intracellular signaling pathways in human retinal pigment epithelial cells exposed to oxidative stress. J Mol Neurosci. 2012;48:493–500.

    Article  CAS  PubMed  Google Scholar 

  63. Ko JA, Hirata J, Yamane K, Sonoda KH, Kiuchi Y. Up-regulation of semaphorin 4A expression in human retinal pigment epithelial cells by PACAP released from cocultured neural cells. Cell Biochem Funct. 2015;33:29–36.

    Article  CAS  PubMed  Google Scholar 

  64. Racz B, Gasz B, Borsiczky B, Gallyas Jr F, Tamas A, Jozsa R, et al. Protective effects of pituitary adenylate cyclase activating polypeptide in endothelial cells against oxidative stress-induced apoptosis. Gen Comp Endocrinol. 2007;153:115–23.

    Article  CAS  PubMed  Google Scholar 

  65. Castorina A, Giunta S, Mazzone V, Cardile V, D’Agata V. Effects of PACAP and VIP on hyperglycemia-induced proliferation in murine microvascular endothelial cells. Peptides. 2010;31:2276–83.

    Article  CAS  PubMed  Google Scholar 

  66. Banki E, Sosnowska D, Tucsek Z, Gautam T, Toth P, Tarantini S, et al. Age-related decline of autocrine pituitary adenylate cyclase-activating polypeptide impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol A Biol Sci Med Sci. 2015;70:665–74.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biological Research Centre, Hungarian Academy of Sciences, Institute of Biophysics, Temesvári krt. 62, Szeged, 6726, Hungary

    Imola Wilhelm & Istvan A. Krizbai

Authors
  1. Imola Wilhelm
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Istvan A. Krizbai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Istvan A. Krizbai .

Editor information

Editors and Affiliations

  1. Department of Anatomy MTA-PTE “Lendulet” PACAP Research Team, University of Pecs, Pecs, Hungary

    Dora Reglodi

  2. Department of Anatomy MTA-PTE “Lendulet” PACAP Research Team, University of Pecs, Pecs, Hungary

    Andrea Tamas

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Wilhelm, I., Krizbai, I.A. (2016). Effects of PACAP on Biological Barriers. In: Reglodi, D., Tamas, A. (eds) Pituitary Adenylate Cyclase Activating Polypeptide — PACAP. Current Topics in Neurotoxicity, vol 11. Springer, Cham. https://doi.org/10.1007/978-3-319-35135-3_26

Download citation

Publish with us

Policies and ethics

Search

Navigation