FIGURE 1.

The integrated extracellular nucleotides/P2 receptor system. A variety of stimuli including volume or flow-mediated stretch, damage, or agonist binding can trigger ATP release into the extracellular space via exocytosis or through specific channels. Ectonucleotidases present on the plasma membrane of the same or adjacent cells rapidly catalyze the sequential hydrolysis of ATP to ADP, AMP, and ultimately adenosine. Adenosine acts on P1 receptors, whereas ATP acts on P2X and some P2Y receptors, while ADP acts on P2Y receptors. Activation of P2X receptors leads to increased ion permeability and an increase in cytosolic calcium; P2X7 and P2X4 receptors are also potentially pore-forming and can increase permeability to larger molecules. P2Y receptor activation couples through G proteins to phospholipase C or adenylate cyclase activation, also leading to increases in intracellular calcium, as well as in cAMP for downstream signaling and effects on renal cell functions. The figure indicates the primary agonists in humans; see TABLE 1 for more details. IP₃, inositol trisphosphate; DAG, diacylglycerol. [Modified from Shirley et al. (474), with permission from Elsevier.]