Emerging roles of purinergic signaling in gastrointestinal epithelial secretion and hepatobiliary function

Taken together, these findings indicate that nucleotides and nucleosides represent potent signaling molecules that contribute importantly to autocrine and paracrine regulation of liver function and gastrointestinal secretion. Moreover, the clinical examples provided by use of adenosine to treat supraventricular tachycardias and ATP/UTP to stimulate airway secretion indicate that pharmacological stimulation of purinergic receptors can be useful therapeutically. This possibility raises a number of intriguing targets for drug development in gastroenterology and emphasizes the need for future studies focusing on the cellular pathway involved. Increasing the concentration of ATP in bile, for example, might serve as a stimulant for cholangiocyte secretion, increasing bile flow and alleviating some of the adverse sequelae of prolonged cholestasis. Selective P1 - and P2-receptor agonists could be used to regulate hepatic metabolism, and the use of receptor antagonists might provide an alternative strategy for limiting tissue damage caused by colonic inflammation. The potential therapeutic opportunities provided by molecular identification of these 18 receptors are just beginning to be defined. However, it is important to emphasize the hurdles that stand in the way of future therapeutic developments. These include understanding the cellular signals responsible for tissue-specific regulation of nucleotide permeability and identifying the specific membrane proteins responsible for ATP release; defining the cellular pathways involved in regulation of the fate of extracellular ATP and controlling the types and quantities of extracellular nucleotides through their catabolism and/or regeneration; identifying the cell-specific functions and individual purinergic receptors and clarifying the cellular logic behind simultaneous expression of multiple P1, P2X, and P2Y recaptor subtypes; and determining the mechanisms responsible for receptor expression and insertion into the plasma membrane and for receptor desensitization, recycling, and termination of signaling. The great progress in understanding the contributors to these diverse aspects of purinergic signaling - ABC family members, nucleotidase, diphosphokinases, and individual receptors - offers many potential options for development of pharmacological strategies that modify gastrointestinal function through specific targeting of the rich and interconnected network of purinergic signaling cascades.