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AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration

Nature volume 407, pages 94–98 (2000)Cite this article

Abstract

The vasopressor angiotensin II regulates vascular contractility and blood pressure through binding to type 1 angiotensin II receptors (AT1; refs 1, 2). Bradykinin, a vasodepressor, is a functional antagonist of angiotensin II (ref. 3). The two hormone systems are interconnected by the angiotensin-converting enzyme, which releases angiotensin II from its precursor and inactivates the vasodepressor bradykinin4. Here we show that the AT1 receptor and the bradykinin (B2) receptor also communicate directly with each other. They form stable heterodimers, causing increased activation of Gαq and Gαi proteins, the two major signalling proteins triggered by AT1. Furthermore, the endocytotic pathway of both receptors changed with heterodimerization. This is the first example of signal enhancement triggered by heterodimerization of two different vasoactive hormone receptors.

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Figure 1: Co-enrichment of AT1 with B2 receptors.
Figure 2: Formation of AT1/B2 heterodimers on HEK-293 cells.
Figure 3: Functional characterization of AT1–B2-receptor heterodimers.
Figure 4: AT1–B2-receptor heterodimerization on A10 smooth muscle cells.

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References

  1. Peach, M. J. Renin-angiotensin system: biochemistry and mechanisms of action. Physiol. Rev. 57, 313–370 (1977).

    Article  CAS  Google Scholar 

  2. Dudley, D. T. et al. Subclasses of angiotensin II binding sites and their functional significance. Mol. Pharmacol. 38, 370– 377 (1990).

    CAS  PubMed  Google Scholar 

  3. Parrat, J. R. Protection of the heart by ischemic preconditioning: mechanisms and possibilities for pharmacological exploitation. Trends Pharmacol. Sci. 5, 19–25 (1994).

    Article  Google Scholar 

  4. Soubrier, F. et al. Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. Proc. Natl Acad. Sci. USA 85, 9386–9390 ( 1988).

    Article  ADS  CAS  Google Scholar 

  5. AbdAlla, S., Jarnagin, K., Müller-Esterl, W. & Quitterer, U. The N-terminal amino group of [Tyr8]bradykinin is bound adjacent to analogous amino acids of the human and rat B2 receptor. J. Biol. Chem. 271, 27382–27387 (1996).

    Article  CAS  Google Scholar 

  6. AbdAlla, S., Zaki, E., Lother, H. & Quitterer, U. Involvement of the amino terminus of the B2 receptor in agonist-induced receptor dimerization. J. Biol. Chem. 274, 26079– 26084 (1999).

    Article  CAS  Google Scholar 

  7. Hein, L. et al. Overexpression of angiotensin AT1 receptor transgene in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block. Proc. Natl Acad. Sci. USA 94, 6391–6396 (1997).

    Article  ADS  CAS  Google Scholar 

  8. Borkowski, J. A. et al. Targeted disruption of a B2 bradykinin receptor gene in mice eliminates bradykinin action in smooth muscle and neurons. J. Biol. Chem. 270, 13706–13710 (1995).

    Article  CAS  Google Scholar 

  9. Zhang, J., Ferguson, S. S. G., Barak, L. S., Menard, L. & Caron, M. G. Dynamin and β-arrestin reveal distinct mechanisms for G protein-coupled receptor internalization. J. Biol. Chem. 271, 118302–18305 (1996).

    Google Scholar 

  10. Ransnäs, L. A., Svoboda, P., Jasper, J. R. & Insel, P. A. Stimulation of β-adrenergic receptors of S49 lymphoma cells redistributes the α subunit of the stimulatory G protein between cytosol and membranes. Proc. Natl Acad. Sci. USA 86, 7900– 7903 (1989).

    Article  ADS  Google Scholar 

  11. MacEwan, D. J., Kim, G. D. & Milligan, G. Analysis of the role of receptor number in defining the intrinsic activity and potency of partial agonists in neuroblastoma x glioma hybrid NG108-15 cells transfected to express differing levels of the human β2-adrenoceptor. Mol. Pharmacol. 48, 316–325 (1995).

    CAS  PubMed  Google Scholar 

  12. Masaki, H. et al. Cardiac-specific overexpression of angiotensin II AT 2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects. J. Clin. Invest. 101, 527–537 (1998).

    Article  CAS  Google Scholar 

  13. Nardone, J. & Hogan, P. G. Delineation of a region in the B2 bradykinin receptor that is essential for high-affinity agonist binding. Proc. Natl Acad. Sci. USA 91, 4417 –4421 (1994).

    Article  ADS  CAS  Google Scholar 

  14. Prado, G. N., Taylor, L. & Polgar, P. Effects of intracellular tyrosine residue mutation and carboxyl terminus truncation on signal transduction and internalization of the rat bradykinin B2 receptor. J. Biol. Chem. 272, 14638–14642 (1997).

    Article  CAS  Google Scholar 

  15. Hebert, T. E. et al. A peptide derived from a β2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation. J. Biol. Chem. 271, 16384–16392 (1996).

    Article  CAS  Google Scholar 

  16. Jordan, B. A. & Devi, L. A. G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399, 697–700 (1999).

    Article  ADS  CAS  Google Scholar 

  17. Romano, C., Yang, W. -L. & O'Malley, K. L. Metabotropic glutamate receptor 5 is a disulfide-linked dimer. J. Biol. Chem. 271, 28612– 28616 (1996).

    Article  CAS  Google Scholar 

  18. Jones, K. A. et al. GABAB receptors function as a heteromeric assembly of the subunits GABABR1 and GABABR2. Nature 396, 674–679 ( 1998).

    Article  ADS  CAS  Google Scholar 

  19. White, J. H. et al. Heterodimerization is required for the formation of a functional GABAB receptor. Nature 396, 679 –682 (1998).

    Article  ADS  CAS  Google Scholar 

  20. Kaupmann, K. et al. GABAB-receptor subtypes assemble into functional heteromeric complexes. Nature 396, 683– 687 (1998).

    Article  ADS  CAS  Google Scholar 

  21. Liu, F. et al. Direct protein–protein coupling enables cross-talk between dopamine D5 and γ-aminobutyric acid A receptors. Nature 493, 274–280 ( 2000).

    Article  ADS  Google Scholar 

  22. Dixon, B. S., Sharma, R. V., Dickerson, T. & Fortune, J. Bradykinin and angiotensin II: activation of protein kinase C in arterial smooth muscle. Am. J. Physiol. 266, 406– 420 (1994).

    Article  Google Scholar 

  23. Tsuchida, S. et al. Potent antihypertrophic effect of the bradykinin B2 receptor system on the renal vasculature. Kidney Int. 56, 509–516 (1999).

    Article  CAS  Google Scholar 

  24. Bascands, J. L. et al. Bradykinin-induced in vitro contraction of rat mesangial cells via a B2 receptor type. Am. J. Physiol. 267, F871–F878 (1994).

    CAS  PubMed  Google Scholar 

  25. Zhuo, J. et al. Localization and interactions of vasoactive peptide receptors in renomedullary interstitial cells of the kidney. Kidney Int. 67, S22–S28. ( 1998).

    Article  CAS  Google Scholar 

  26. Quitterer, U. & Lohse, M. J. Crosstalk between Gα i- and Gαq-coupled receptors is mediated by Gβγ exchange. Proc. Natl Acad. Sci. USA 96, 10626–10631 (1999).

    Article  ADS  CAS  Google Scholar 

  27. Quitterer, U., Zaki, E. & AbdAlla, S. Investigation of the extracellular accessibility of the connecting loop between membrane domains I and II of the bradykinin B 2 receptor. J. Biol. Chem. 274, 14773 –14778 (1999).

    Article  CAS  Google Scholar 

  28. Mastro, R. & Hall, M. Protein delipidation and precipitation by tri-n-butylphosphate, acetone, and methanol treatment for isoelectric focusing and two-dimensional gel electrophoresis. Anal. Biochem. 273, 313–315 (1999).

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Acknowledgements

We thank B. Nürnberg, for anti-Gα-common antibodies, and J. Heukeshoven for helpful advice on high-resolution electrophoresis of hydrophobic proteins. This work was supported in part by the Deutsche Forschungsgemeinschaft.

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Authors and Affiliations

  1. Genetics Engineering and Biotechnology Research Institute, Manchiat El-Olama, El-Dekheela , Alexandria, Egypt

    Said AbdAlla

  2. Heinrich Pette Institut, Martinistraβe 52, Hamburg, 20251, Germany

    Heinz Lother

  3. Institut für Pharmakologie, Versbacher Straβe 9, Würzburg, 97078, Germany

    Ursula Quitterer

Authors
  1. Said AbdAlla
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  2. Heinz Lother
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  3. Ursula Quitterer
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Correspondence to Ursula Quitterer.

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AbdAlla, S., Lother, H. & Quitterer, U. AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature 407, 94–98 (2000). https://doi.org/10.1038/35024095

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