Extracellular adenosine is a ubiquitous signaling molecule that modulates a wide array of biological processes. There are currently four known sub-types of adenosine receptors: A₁, A_2A, A_2B and A₃.

The adenosine A_2B receptor is a typical class A, G protein-coupled receptor with seven transmembrane segments, an extracellular N-terminus and an intracellular C-terminus. Adenosine A_2BR causes an increase in intracellular cAMP levels by coupling mainly to G_s proteins, resulting in the activation of adenylyl cyclase¹ and subsequent activation of PKA and other cAMP effectors such as Epac. In addition, the A_2BR couples to G_q and activates the PLC pathway that mediates several crucial functions of A_2BR. A_2BR also couples to the MAPK and arachidonic acid signaling pathways and regulates membrane ion channels probably through G-protein βγ subunits.

Multiple molecules that bind to A_2BR have been identified in an effort to understand the receptor’s function and regulation. NFκB1/p105 is a member of the NFκB family of proteins that perform regulatory functions in diverse biological processes such as inflammation and cell survival and differentiation, as well as in various diseases. Interestingly, Although A_2BR activation by adenosine produces pro-inflammatory effects the receptor also binds to specific sites on p105, prevents the poly-ubiquitination and degradation of the p105 protein and inhibits NFκB activation thus reducing inflammation.

A_2BR is highly expressed in various types of tumor cells or tissues and promotes tumor-cell proliferation. A_2BR was found to be overexpressed in colorectal carcinoma cells and tissues, and inhibition of A_2BR blocks the proliferation of colon cancer cells. A_2BR has been implicated in the pathophysiology of vascular diseases, renal disease and diabetes².