Intracellular Accumulation and Nuclear Trafficking of Angiotensin II and the Angiotensin II Type 1 Receptor

Conference paper


Despite the fact that the concept of an intracellular or intracrine renin-angiotensin system has gained general acceptance over the last decade, several questions continue to trouble this research area. Empirical evidence supports the existence of intracellular angiotensin II peptide and nuclear angiotensin II type 1 receptor, translocation of the plasma membrane receptor to the nucleus, and functionality of the intracellular RAS components. However, the mechanism by which intracellular angiotensin II is generated or alternatively internalized and reutilized, and the means by which the AT1 receptor is transported to the nuclear membrane remain unclear. This paper reviews some of the relevant literature and ideas related to intracellular trafficking of angiotensin II and its cognate receptors and presents new supporting data for alternative mechanisms by which the receptors and angiotensin II might accumulate in the nuclear compartment.


Nuclear Membrane Recycling Pathway Outer Nuclear Membrane Enhanced Cyan Fluorescent Protein Intracellular Synthesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Robertson AL, Jr, Khairallah PA. Angiotensin II: rapid localization in nuclei of smooth and cardiac muscle. Science. Jun 11 1971;172(988):1138–1139.PubMedCrossRefGoogle Scholar
  2. 2.
    Re RN, MacPhee AA, Fallon JT. Specific nuclear binding of angiotensin II by rat liver and spleen nuclei. Clin Sci (Lond). Dec 1981;61(Suppl 7):245s–247s.Google Scholar
  3. 3.
    Booz GW, Conrad KM, Hess AL, et al. Angiotensin-II-binding sites on hepatocyte nuclei. Endocrinology. Jun 1992;130(6):3641–3649.PubMedCrossRefGoogle Scholar
  4. 4.
    Eggena P, Zhu JH, Clegg K, et al. Nuclear angiotensin receptors induce transcription of renin and angiotensinogen mRNA. Hypertension. Oct 1993;22(4):496–501.PubMedGoogle Scholar
  5. 5.
    Jimenez E, Vinson GP, Montiel M. Angiotensin II (AII)-binding sites in nuclei from rat liver: partial characterization of the mechanism of AII accumulation in nuclei. J Endocrinol. Dec 1994;143(3):449–453.PubMedCrossRefGoogle Scholar
  6. 6.
    Tang SS, Rogg H, Schumacher R, et al. Characterization of nuclear angiotensin-II-binding sites in rat liver and comparison with plasma membrane receptors. Endocrinology. Jul 1992;131(1):374–380.PubMedCrossRefGoogle Scholar
  7. 7.
    Hunyady L, Baukal AJ, Gaborik Z, et al. Differential PI 3-kinase dependence of early and late phases of recycling of the internalized AT1 angiotensin receptor. J Cell Biol. Jun 24 2002;157(7):1211–1222.PubMedCrossRefGoogle Scholar
  8. 8.
    Bremnes T, Paasche JD, Mehlum A, et al. Regulation and intracellular trafficking pathways of the endothelin receptors. J Biol Chem. Jun 9 2000;275(23):17596–17604.PubMedCrossRefGoogle Scholar
  9. 9.
    Paasche JD, Attramadal T, Sandberg C, et al. Mechanisms of endothelin receptor subtype-specific targeting to distinct intracellular trafficking pathways. J Biol Chem. Sep 7 2001;276(36):34041–34050.PubMedCrossRefGoogle Scholar
  10. 10.
    Boivin B, Chevalier D, Villeneuve LR, et al. Functional endothelin receptors are present on nuclei in cardiac ventricular myocytes. J Biol Chem. Aug 1 2003;278(31):29153–29163.PubMedCrossRefGoogle Scholar
  11. 11.
    Bkaily G, Choufani S, Hassan G, et al. Presence of functional endothelin-1 receptors in nuclear membranes of human aortic vascular smooth muscle cells. J Cardiovasc Pharmacol. Nov 2000;36(5 Suppl 1):S414–S417.PubMedGoogle Scholar
  12. 12.
    Tabellini G, Bortul R, Santi S, et al. Diacylglycerol kinase-theta is localized in the speckle domains of the nucleus. Exp Cell Res. Jul 1 2003;287(1):143–154.PubMedCrossRefGoogle Scholar
  13. 13.
    Waugh MG, Hsuan JJ. EGF receptors as transcription factors: ridiculous or sublime? Nat Cell Biol. Sep 2001;3(9):E209–E211.PubMedCrossRefGoogle Scholar
  14. 14.
    Heldin CH, Ericsson J. Signal transduction. RIPping tyrosine kinase receptors apart. Science. Dec 7 2001;294(5549):2111–2113.PubMedCrossRefGoogle Scholar
  15. 15.
    Radulescu RT. Insulin receptor alpha-subunit: a putative gene regulatory molecule. Med Hypotheses. Aug 1995;45(2):107–111.PubMedCrossRefGoogle Scholar
  16. 16.
    Seol KC, Kim SJ. Nuclear matrix association of insulin receptor and IRS-1 by insulin in osteoblast-like UMR-106 cells. Biochem Biophys Res Commun. Jul 11 2003;306(4):898–904.PubMedCrossRefGoogle Scholar
  17. 17.
    Wu A, Sciacca L, Baserga R. Nuclear translocation of insulin receptor substrate-1 by the insulin receptor in mouse embryo fibroblasts. J Cell Physiol. Jun 2003;195(3):453–460.PubMedCrossRefGoogle Scholar
  18. 18.
    Bannykh SI, Rowe T, Balch WE. The organization of endoplasmic reticulum export complexes. J Cell Biol. Oct 1996;135(1):19–35.PubMedCrossRefGoogle Scholar
  19. 19.
    Bejcek BE, Li DY, Deuel TF. Transformation by v-sis occurs by an internal autoactivation mechanism. Science. Sep 29 1989;245(4925):1496–1499.PubMedCrossRefGoogle Scholar
  20. 20.
    Chi TH, Crabtree GR. Perspectives: signal transduction. Inositol phosphates in the nucleus. Science. Mar 17 2000;287(5460):1937–1939.PubMedCrossRefGoogle Scholar
  21. 21.
    D’Santos CS, Clarke JH, Irvine RF, et al. Nuclei contain two differentially regulated pools of diacylglycerol. Curr Biol. Apr 22 1999;9(8):437–440.PubMedCrossRefGoogle Scholar
  22. 22.
    Irvine RF. Inositol lipids in cell signalling. Curr Opin Cell Biol. Apr 1992;4(2):212–219.PubMedCrossRefGoogle Scholar
  23. 23.
    Irvine RF. Nuclear lipid signalling. Nat Rev Mol Cell Biol. May 2003;4(5):349–360.PubMedCrossRefGoogle Scholar
  24. 24.
    Mazzotti G, Zini N, Rizzi E, et al. Immunocytochemical detection of phosphatidylinositol 4,5-bisphosphate localization sites within the nucleus. J Histochem Cytochem. Feb 1995;43(2):181–191.PubMedGoogle Scholar
  25. 25.
    Raben DM, Baldassare JJ. Nuclear envelope signaling-role of phospholipid metabolism. Eur J Histochem. 2000;44(1):67–80.PubMedGoogle Scholar
  26. 26.
    Martelli AM, Tabellini G, Bortul R, et al. Enhanced nuclear diacylglycerol kinase activity in response to a mitogenic stimulation of quiescent Swiss 3T3 cells with insulin-like growth factor I. Cancer Res. Feb 15 2000;60(4):815–821.PubMedGoogle Scholar
  27. 27.
    Tanaka K, Horiguchi K, Yoshida T, et al. Evidence that a phosphatidylinositol 3,4,5-trisphosphate-binding protein can function in nucleus. J Biol Chem. Feb 12 1999;274(7):3919–3922.PubMedCrossRefGoogle Scholar
  28. 28.
    Zini N, Sabatelli P, Faenza I, et al. Interleukin-1 alpha induces variations of the intranuclear amount of phosphatidylinositol 4,5-bisphosphate and phospholipase C beta 1 in human osteosarcoma Saos-2 cells. Histochem J . Jul 1996;28(7):495–504.PubMedCrossRefGoogle Scholar
  29. 29.
    Marrache AM, Gobeil F, Zhu T, et al. Intracellular signaling of lipid mediators via cognate nuclear G protein-coupled receptors. Endothelium. Jan–Apr 2005;12(1–2):63–72.PubMedCrossRefGoogle Scholar
  30. 30.
    Cook JL, Mills SJ, Naquin R, et al. Nuclear accumulation of the AT1 receptor in a rat vascular smooth muscle cell line: effects upon signal transduction and cellular proliferation. J Mol Cell Cardiol. May 2006;40(5):696–707.PubMedCrossRefGoogle Scholar
  31. 31.
    Cook JL, Mills SJ, Naquin RT, et al. Cleavage of the angiotensin II type 1 receptor and nuclear accumulation of the cytoplasmic carboxy-terminal fragment. Am J Physiol Cell Physiol. Apr 2007;292(4):C1313–C1322.PubMedCrossRefGoogle Scholar
  32. 32.
    Ataman B, Ashley J, Gorczyca D, et al. Nuclear trafficking of Drosophila Frizzled-2 during synapse development requires the PDZ protein dGRIP. Proc Natl Acad Sci USA. May 16 2006;103(20):7841–7846.PubMedCrossRefGoogle Scholar
  33. 33.
    Carpenter G. Nuclear localization and possible functions of receptor tyrosine kinases. Curr Opin Cell Biol. Apr 2003;15(2):143–148.PubMedCrossRefGoogle Scholar
  34. 34.
    Clevenger CV. Nuclear localization and function of polypeptide ligands and their receptors: a new paradigm for hormone specificity within the mammary gland? Breast Cancer Res. 2003;5(4):181–187.PubMedCrossRefGoogle Scholar
  35. 35.
    Krolewski JJ. Cytokine and growth factor receptors in the nucleus: what's up with that? J Cell Biochem. Jun 1 2005;95(3):478–487.PubMedCrossRefGoogle Scholar
  36. 36.
    Wells A, Marti U. Signalling shortcuts: cell-surface receptors in the nucleus? Nat Rev Mol Cell Biol. Sep 2002;3(9):697–702.PubMedCrossRefGoogle Scholar
  37. 37.
    Lu D, Yang H, Shaw G, et al. Angiotensin II-induced nuclear targeting of the angiotensin type 1 (AT1) receptor in brain neurons. Endocrinology. Jan 1998;139(1):365–375.PubMedCrossRefGoogle Scholar
  38. 38.
    Morinelli TA, Raymond JR, Baldys A, et al. Identification of a putative nuclear localization sequence within ANG II AT(1A) receptor associated with nuclear activation. Am J Physiol Cell Physiol. Apr 2007;292(4):C1398–C1408.PubMedCrossRefGoogle Scholar
  39. 39.
    Tsai B, Ye Y, Rapoport TA. Retro-translocation of proteins from the endoplasmic reticulum into the cytosol. Nat Rev Mol Cell Biol. Apr 2002;3(4):246–255.PubMedCrossRefGoogle Scholar
  40. 40.
    VanSlyke JK, Musil LS. Dislocation and degradation from the ER are regulated by cytosolic stress. J Cell Biol. Apr 29 2002;157(3):381–394.PubMedCrossRefGoogle Scholar
  41. 41.
    Licea H, Walters MR, Navar LG. Renal nuclear angiotensin II receptors in normal and hypertensive rats. Acta Physiol Hung. 2002;89(4):427–438.PubMedCrossRefGoogle Scholar
  42. 42.
    Re R, Parab M. Effect of angiotensin II on RNA synthesis by isolated nuclei. Life Sci. Feb 13 1984;34(7):647–651.PubMedCrossRefGoogle Scholar
  43. 43.
    Re RN, Vizard DL, Brown J, et al. Angiotensin II receptors in chromatin fragments generated by micrococcal nuclease. Biochem Biophys Res Commun. Feb 29 1984;119(1):220–227.PubMedCrossRefGoogle Scholar
  44. 44.
    Sherrod M, Liu X, Zhang X, et al. Nuclear localization of angiotensinogen in astrocytes. Am J Physiol Regul Integr Comp Physiol. Feb 2005;288(2):R539–R546.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Molecular GeneticsOchsner Clinic FoundationNew OrleansUSA
  2. 2.Ochsner Clinic FoundationNew OrleansUSA

Personalised recommendations