E. B. Hershberg Award: Taming Inflammation by Tuning Purinergic Signaling.

The author presents his personal story from early contributions in purinergic receptor research to present-day structure-guided medicinal chemistry. Modulating purinergic signaling (encompassing pyrimidine nucleotides as well) and other nucleoside targets with small molecules is fruitful for identifying new directions for therapeutic intervention. Purinergic signaling encompasses four adenosine receptors, eight P2Y receptors that respond to various extracellular nucleotides, and trimeric P2X receptors that respond mainly to ATP. Each organ and tissue in the body expresses some combination of this family of cell-surface receptors, along with the enzymes and transporters that form, degrade, and process the native nucleoside and nucleotide agonists. The purinergic signaling system responds to physiological stress to an organ, for example by increasing the energy supply or decreasing the energy demand. The receptors are widespread on immune cells, such that P2Y and P2X receptor activation boosts the immune response when and where it is needed, for example to repel infection. In contrast, the adenosine receptors, which are activated later in the process─as stress-elevated ATP is hydrolyzed locally to adenosine by ectonucleotidases─tend to put the brakes on inflammation and can be used to correct an imbalance in pro- versus anti-inflammatory signals, such as in chronic pain. Hypoxia activates the immunosuppressive extracellular adenosine-A