Adenosine signaling via A2B receptor regulates erythrocyte 2,3‐bisphosphate induction at high altitude (885.6)

Abstract

To function effectively in O2 uptake, and unload, erythrocytes rely on sophisticated regulation of hemoglobin (Hb)‐O2 affinity by allosteric modulators. One of the best known allosteric modulators is 2,3‐bisphophosphoglycerate (2,3‐BPG). Earlier studies demonstrated that erythrocyte 2,3‐BPG levels are elevated at a high altitude. However, what triggers its induction at high altitude is unknown. To address this question, we recruited 24 individuals and placed them at high altitude for different time points. Here we report that 1) Plasma adenosine and erythrocyte 2,3‐BPG levels were significantly elevated in normal individuals at high altitude after 24 hours compared to sea level; 2) their levels are further enhanced at high altitude after 16 days; 3) Elevated circulating adenosine levels significantly correlated with increased erythrocyte 2,3‐DPG levels in normal individuals at high altitude. Next, we provide in vitro evidence that adenosine signaling via A2B receptor (ADORA2B) directly induced 2,3‐BPG production in a protein kinase A‐dependent manner in cultured human erythrocytes. Finally, we provide genetic and pharmacological evidence that that ADORA2B is essential for elevated adenosine induced 2,3‐BPG production and triggers O2 release in mice. Taken together, we reveal ADORA2B signaling cascade regulating erythrocyte 2,3‐BPG induction as a function of altitude and identify new targets to enhance O2 release under hypoxia conditions.Grant Funding Source: NIH