Hypoxia sensing through β-adrenergic receptors

Abstract

Life-sustaining responses to low oxygen, or hypoxia, depend on signal transduction by HIFs, but the underlying mechanisms by which cells sense hypoxia are not completely understood. Based on prior studies suggesting a link between the β-adrenergic receptor (β-AR) and hypoxia responses, we hypothesized that the β-AR mediates hypoxia sensing and is necessary for HIF-1α accumulation. Beta blocker treatment of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo. Likewise, beta blocker treatment of primary human endothelial cells in vitro decreased hypoxia-mediated HIF-1α accumulation and binding to target genes and the downstream hypoxia-inducible gene expression. In mechanistic studies, cAMP-activated PKA and/or GPCR kinases (GRK), which both participate in β-AR signal transduction, were investigated. Direct activation of cAMP/PKA pathways did not induce HIF-1α accumulation, and inhibition of PKA did not blunt HIF-1α induction by hypoxia. In contrast, pharmacological inhibition of GRK, or expression of a GRK phosphorylation-deficient β-AR mutant in cells, blocked hypoxia-mediated HIF-1α accumulation. Mass spectrometry-based quantitative analyses revealed a hypoxia-mediated β-AR phosphorylation barcode that was different from the classical agonist phosphorylation barcode. These findings indicate that the β-AR is fundamental to the molecular and physiological responses to hypoxia.

Impact of paroxetine on proximal β-adrenergic receptor signaling

“…Although there are no reports directly comparing the impact of paroxetine on receptor phosphorylation amongst distinct GPCRs, in terms of relative efficacy paroxetine inhibited ligand-induced β2AR phosphorylation in our study with an IC 50 of ~6 μM, compared to an IC 50 of ~30 μM for the TRHR previously reported 7 , possibly suggesting more reliance upon GRK2 for β2AR versus TRHR phosphorylation. Of note, a recent study showed that β2AR phosphorylation induced by hypoxic stress was also decreased by the GRK2 inhibitor 182200 22 , however the concentration of inhibitor 182200 required to partially block the response was 125 μM, as compared to the 10–30 μM range of paroxetine sufficient to almost completely abrogate β2AR phosphorylation in our study. More in line with our study, Lowe et al demonstrated a similar impact of 30 μM Takeda Cmpd 101 on ligand-induced μ-opioid receptor phosphorylation, βarr2 recruitment and receptor internalization 23 .…”

Hypoxia and the hypoxia inducible factor 1α activate protein kinase A by repressing RII beta subunit transcription

“…This shifted the focus on the role of PKA-mediated regulation of HIF in models of congestive heart failure, as PKA plays an important role for signal transduction through β-adrenergic receptors in cardiomyocytes. Furthermore, inhibition of β-adrenergic receptors reduces the hypoxia-induced stabilization of HIF-1α in primary human endothelial cells [69]. Our study demonstrates that the PKA-HIF-1α interaction is reciprocal, with HIF-1α exerting a positive feedback on PKA.…”

Pulmonary arterial hypertension treatment with carvedilol for heart failure: a randomized controlled trial

“…In addition, βARs have recently been implicated in hypoxia sensing (52). Cheong et al have shown that β-blockade suppresses hypoxic induction of gene expression, such as erythropoietin (52). Thus, β-blockade may also directly abrogate hypoxia sensing in the PAH myocardium.…”