Introduction of ADORA2B

Adenosine receptor A_2b (ADORA2B) is a protein that in human is encoded by the ADORA2B gene. ADORA2B is a member of the adenosine receptor group of G-protein-coupled receptors that also includes A₁, A_2A, and A₃. The ADORA2B gene, which is located near the Smith-Magenis syndrome region on chromosome 17, encodes an adenosine receptor that is a member of the G protein-coupled receptor superfamily. This integral membrane protein not only stimulates adenylate cyclase activity in the presence of adenosine but also interacts with netrin-1 that is involved in axon elongation. Among the related pathways of the protein, ADORA2B are Nucleotide-like (purinergic) receptors and Peptide ligand-binding receptors. Gene Ontology (GO) annotations related to this gene include G-protein coupled receptor activity and G-protein coupled adenosine receptor activity. An important paralog of this gene is ADORA2A.

Function of ADORA2B Membrane Protein

Activation of ADORA2B occurs with high extracellular adenosine concentration, such as in inflammation or hypoxia. These conditions are generated in the tumor environment. ADORA2B not only exerts immunomodulatory effects that protect tumor cells but also participates in different events, such as angiogenesis and metastasis. ADORA2B receptors display high expression levels in the bladder, colon, and cecum, with lower levels in the blood vessels, lung, and eye. Activated macrophages (AAMs) expressing ADORA2B have been implicated in mediating adenosine's effects in Idiopathic pulmonary fibrosis (IPF) and HIF1A up-regulates the ADORA2B receptor on alternatively activated macrophages and contributes to pulmonary fibrosis. ADORA2B plays an important anti-inflammatory role in the lung. CXCR4- and CXCR7-inhibition had a synergistic effect in acute pulmonary inflammation, which depended on A2B-receptor signaling. Meanwhile, A2BAR signaling may play a protective role in countering ischemic lung injury.

Fig.1 A Model for the Stimulation of Glycolysis in the Heart by Adora2b. (Lopaschuk, 2012)

Application of ADORA2B Membrane Protein in Literature

1. Philip K., et al. HIF1A up-regulates the ADORA2B receptor on alternatively activated macrophages and contributes to pulmonary fibrosis. FASEB J. 2017, 31(11): 4745-4758. PubMed ID: 28701304

This article reports that HIF1A up-regulates the ADORA2B receptor on alternatively activated macrophages and contributes to pulmonary fibrosis. ADORA2B deletion or pharmacological antagonism along with HIF1A inhibition disrupts AAM differentiation and subsequent IL-6 production in cultured macrophages.

2. Konrad FM., et al. Inhibition of SDF-1 receptors CXCR4 and CXCR7 attenuates acute pulmonary inflammation via the adenosine A2B-receptor on blood cells. Cell Death Dis. 2017, 8(5): e2832. PubMed ID: 28542132

Authors in this group investigated the particular role of CXCR4- and CXCR7-inhibition and the potential link to the adenosine A2B-receptor, which plays an important anti-inflammatory role in the lung.

3. Densmore JC., et al. Lung injury pathways: Adenosine receptor 2B signaling limits development of ischemic bronchiolitis obliterans organizing pneumonia. Exp Lung Res. 2017, 43(1): 38-48. PubMed ID: 28266889

This article studies the role of adenosine signaling in bronchiolitis obliterans organizing pneumonia (BOOP) resulting from unilateral lung ischemia. It shows that A2BAR signaling may play a protective role in countering ischemic lung injury.

4. Mølck C., et al. The A_2b adenosine receptor antagonist PSB-603 promotes oxidative phosphorylation and ROS production in colorectal cancer cells via adenosine receptor-independent mechanism. Cancer Lett. 2016, 383(1): 135-143. PubMed ID: 27693637

Authors in this group analyze the contribution of the A_2b-AR to the behavior of colorectal cancer cells. The results show that the A_2b-AR antagonist, PSB-603, may have clinical value as anti-colorectal cancer therapeutic.

5. Sorrentino C., et al. Activation of the A2B adenosine receptor in B16 melanomas induces CXCL12 expression in FAP-positive tumor stromal cells, enhancing tumor progression. Oncotarget. 2016, 7(39): 64274-64288. PubMed ID: 27590504

This article reveals an important role for A2BR in stimulating FGF2 and CXCL12 expression in melanoma-associated fibroblasts, which contributes to creating a tumor-promoting microenvironment.

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Reference

1. Lopaschuk GD and Jaswal JS. (2012). A role for period 2 in cardioprotection. Cell Metab. 16(1), 2-4.

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