Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Sci. Signal., 7 July 2009
Vol. 2, Issue 78, p. ra33
[DOI: 10.1126/scisignal.2000444]

RESEARCH ARTICLES

Editor's Summary

Oxygen-Regulated GPCR Down-Regulation
Adrenergic signaling through β-adrenergic receptors regulates cardiovascular and pulmonary function, and dysfunction of β-adrenergic receptor signaling is associated with diseases such as heart failure and asthma. The responsiveness of a cell to adrenergic signaling depends substantially on the abundance and location of the receptors and is controlled by the processes of desensitization, a transient decrease in responsiveness of the receptor, and down-regulation, a prolonged decrease in responsiveness through internalization and subsequent degradation of the receptors. Xie et al. now show that oxygen regulates the stability of the β2 type of adrenergic receptor, which mediates the integrated physiological response to hypoxic conditions by enhancing cardiac contractility; peripheral vasodilation, which increases O2 delivery; and alveolar fluid clearance, which increases O2 uptake. Furthermore, they show that oxygen-regulated down-regulation of the receptors occurs through receptor proline hydroxylation by the dioxygenase EGLN3 and ubiquitylation by the von Hippel–Lindau tumor suppressor protein (pVHL)–E3 ligase complex, which also controls hypoxia-inducible factor stability, and that this process is inhibited by hypoxia.

Citation: L. Xie, K. Xiao, E. J. Whalen, M. T. Forrester, R. S. Freeman, G. Fong, S. P. Gygi, R. J. Lefkowitz, J. S. Stamler, Oxygen-Regulated β2-Adrenergic Receptor Hydroxylation by EGLN3 and Ubiquitylation by pVHL. Sci. Signal. 2, ra33 (2009).

Read the Full Text

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
p62/SQSTM1 regulates cellular oxygen sensing by attenuating PHD3 activity through aggregate sequestration and enhanced degradation.
K. Rantanen, J.-P. Pursiheimo, H. Hogel, P. Miikkulainen, J. Sundstrom, and P. M. Jaakkola (2013)
J. Cell Sci. 126, 1144-1154
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 20 November 2012.
R. J. Lefkowitz and A. M. VanHook (2012)
Science Signaling 5, pc26
   Abstract »    Full Text »
Transmembrane prolyl 4-hydroxylase is a fourth prolyl 4-hydroxylase regulating EPO production and erythropoiesis.
A. Laitala, E. Aro, G. Walkinshaw, J. M. Maki, M. Rossi, M. Heikkila, E.-R. Savolainen, M. Arend, K. I. Kivirikko, P. Koivunen, et al. (2012)
Blood 120, 3336-3344
   Abstract »    Full Text »    PDF »
Roles of individual prolyl-4-hydroxylase isoforms in the first 24 hours following transient focal cerebral ischaemia: insights from genetically modified mice.
R.-L. Chen, S. Nagel, M. Papadakis, T. Bishop, P. Pollard, P. J. Ratcliffe, C. W. Pugh, and A. M. Buchan (2012)
J. Physiol. 590, 4079-4091
   Abstract »    Full Text »    PDF »
Prostaglandin EP1 Receptor Down-regulates Expression of Cyclooxygenase-2 by Facilitating Its Proteasomal Degradation.
A. Haddad, G. Flint-Ashtamker, W. Minzel, R. Sood, G. Rimon, and L. Barki-Harrington (2012)
J. Biol. Chem. 287, 17214-17223
   Abstract »    Full Text »    PDF »
Regulation of Cellular Levels of Sprouty2 Protein by Prolyl Hydroxylase Domain and von Hippel-Lindau Proteins.
K. Anderson, K. A. Nordquist, X. Gao, K. C. Hicks, B. Zhai, S. P. Gygi, and T. B. Patel (2011)
J. Biol. Chem. 286, 42027-42036
   Abstract »    Full Text »    PDF »
Rescue of the mutant CFTR chloride channel by pharmacological correctors and low temperature analyzed by gene expression profiling.
E. Sondo, V. Tomati, E. Caci, A. I. Esposito, U. Pfeffer, N. Pedemonte, and L. J. V. Galietta (2011)
Am J Physiol Cell Physiol 301, C872-C885
   Abstract »    Full Text »    PDF »
Ascorbic acid regulates osterix expression in osteoblasts by activation of prolyl hydroxylase and ubiquitination-mediated proteosomal degradation pathway.
W. Xing, S. Pourteymoor, and S. Mohan (2011)
Physiol Genomics 43, 749-757
   Abstract »    Full Text »    PDF »
{beta}2-Adrenergic Receptor Lysosomal Trafficking Is Regulated by Ubiquitination of Lysyl Residues in Two Distinct Receptor Domains.
K. Xiao and S. K. Shenoy (2011)
J. Biol. Chem. 286, 12785-12795
   Abstract »    Full Text »    PDF »
Deficiency of a Transmembrane Prolyl 4-Hydroxylase in the Zebrafish Leads to Basement Membrane Defects and Compromised Kidney Function.
J. Hyvarinen, M. Parikka, R. Sormunen, M. Ramet, K. Tryggvason, K. I. Kivirikko, J. Myllyharju, and P. Koivunen (2010)
J. Biol. Chem. 285, 42023-42032
   Abstract »    Full Text »    PDF »
International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors.
G. Schulte (2010)
Pharmacol. Rev. 62, 632-667
   Abstract »    Full Text »    PDF »
{beta}2- but not {beta}1-adrenoceptor activation modulates intracellular oxygen availability.
J. Li, B. Yan, Z. Huo, Y. Liu, J. Xu, Y. Sun, Y. Liu, D. Liang, L. Peng, Y. Zhang, et al. (2010)
J. Physiol. 588, 2987-2998
   Abstract »    Full Text »    PDF »
Cullins and Cancer.
J. Lee and P. Zhou (2010)
Genes & Cancer 1, 690-699
   Abstract »    Full Text »    PDF »
Aiming Straight for the Heart: Prolyl Hydroxylases Set the BAR.
J. A. Garcia (2009)
Science Signaling 2, pe70
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882