The resurgence of A2B adenosine receptor signaling

Abstract

Since its discovery as a low-affinity adenosine receptor (AR), the A2B receptor (A2BAR), has proven enigmatic in its function. The previous discovery of the A2AAR, which shares many similarities with the A2BAR but demonstrates significantly greater affinity for its endogenous ligand, led to the original perception that the A2BAR was not of substantial physiologic relevance. In addition, lack of specific pharmacological agents targeting the A2BAR made its initial characterization challenging. However, the importance of this receptor was reconsidered when it was observed that the A2BAR is highly transcriptionally regulated by factors implicated in inflammatory hypoxia. Moreover, the notion that during ischemia or inflammation extracellular adenosine is dramatically elevated to levels sufficient for A2BAR activation, indicated that A2BAR signaling may be important to dampen inflammation particularly during tissue hypoxia. In addition, the recent advent of techniques for murine genetic manipulation along with development of pharmacological agents with enhanced A2BAR specificity has provided invaluable tools for focused studies on the explicit role of A2BAR signaling in different disease models. Currently, studies performed with combined genetic and pharmacological approaches have demonstrated that A2BAR signaling plays a tissue protective role in many models of acute diseases e.g. myocardial ischemia, or acute lung injury. These studies indicate that the A2BAR is expressed on a wide variety of cell types and exerts tissue/cell specific effects. This is an important consideration for future studies where tissue or cell type specific targeting of the A2BAR may be used as therapeutic approach.

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

“…As first step, we induced diabetic nephropathy in previously described Adora2b 2/2 mice. 23,[28][29][30][31][48][49][50][51] Similar to the preceding studies in Cd73 2/2 mice, we observed a more severe degree of diabetic nephropathy in Adora2b 2/2 mice without differences regarding systolic BP and blood glucose levels (Supplemental Figure 4, A and B), but a more severe degree of body weight loss ( Figure 5A), increased kidney weight (Figure 5B), and elevated urine (Figure 5C) and drinking ( Figure 5D) volumes. Determination of the GFR showed a more severe hyperfiltration in Adora2b 2/2 mice compared with diabetic control mice ( Figure 5E).…”

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

“…Thus, the present findings demonstrating that dipyridamole-mediated kidney protection is predominantly mediated by Adora2b expressed on vascular endothelia are somewhat surprising. This could - at least in partbe related to the fact that the Adora2b is the most insensitive AR, requiring adenosine concentrations in the micromolar range (57,58), whereas activation of Adora1a or Adora2a occurs at much lower adenosine concentrations. It is conceivable that particularly experimental conditions such as Ent1 inhibition or deletion during AKI are associated with elevations in extracellular adenosine sufficient to activate Adora2b.…”

Adenosine enhances progenitor cell recruitment and nerve growth via its A2B receptor during adult fin regeneration

“…We provide evidence that the A2B receptor is involved in the regulation of compensatory proliferation shortly after amputation, and this correlates with findings in A2B receptor physiology [59]. Indeed, it has been shown that A2B receptor expression is induced by hypoxia and that A2B signalling plays a tissue protective role in many models [60].…”