A adenosine receptor signaling and regulation.

The A adenosine receptor (AR) 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 AR. The AR is coupled to both G and G, as well as G 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 AR endogenously at high levels, suggesting its potentially important role in asthma, cancer, diabetes, and other conditions. The AR 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 AR antagonism contributes to their therapeutic effects or side effects. The AR is required in ischemic cardiac preconditioning by adenosine. Both AR and protein kinase C (PKC) contribute to cardioprotection, and both modes of AR signaling can be blocked by AR antagonists. Inhibitors of PKC and AR are in clinical cancer trials. Sulforaphane and other isothiocyanates from cruciferous vegetables such as broccoli and cauliflower have been reported to inhibit AR signaling via reaction with an intracellular AR cysteine residue (C210). A full, AR-selective agonist, critical to elucidate many controversial roles of the AR, is still not available, although agonist-bound AR structures have recently been reported.