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Sci. Signal., 7 July 2009
Vol. 2, Issue 78, p. ra33
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).