A_2B adenosine receptor signaling and regulation

The A_2B adenosine receptor (A_2BR) is one of the four adenosine-activated G protein-coupled receptors. In addition to adenosine, protein kinase C (PKC) was recently found to activate the A_2BR. The A_2BR is coupled to both G_s and G_i, as well as G_q proteins in some cell types. Many primary cells and cell lines, such as bladder and breast cancer, bronchial smooth muscle, skeletal muscle, and fat cells, express the A_2BR endogenously at high levels, suggesting its potentially important role in asthma, cancer, diabetes, and other conditions. The A_2BR has been characterized as both pro- and anti-inflammatory, inducing cell type-dependent secretion of IL-6, IL-8, and IL-10. Theophylline and enprofylline have long been used for asthma treatment, although it is still not entirely clear if their A_2BR antagonism contributes to their therapeutic effects or side effects. The A_2BR is required in ischemic cardiac preconditioning by adenosine. Both A_2BR and protein kinase C (PKC) contribute to cardioprotection, and both modes of A_2BR signaling can be blocked by A_2BR antagonists. Inhibitors of PKC and A_2BR are in clinical cancer trials. Sulforaphane and other isothiocyanates from cruciferous vegetables such as broccoli and cauliflower have been reported to inhibit A_2BR signaling via reaction with an intracellular A_2BR cysteine residue (C210). A full, A_2BR-selective agonist, critical to elucidate many controversial roles of the A_2BR, is still not available, although agonist-bound A_2BR structures have recently been reported.