Purinergic regulation of duodenal surface pH and ATP concentration: implications for mucosal defence, lipid uptake and cystic fibrosis

Abstract

The duodenum secretes HCO₃⁻ as part of a multi-layered series of defence mechanisms against damage from luminal acid. In the 1980s, an alkaline surface layer was measured over the mucosa which correlated with the rate of HCO₃⁻ secretion. As all biological processes are regulated, we investigated how the alkaline pH of the surface layer was maintained. As the ecto-phosphorylase alkaline phosphatase (AP) is highly expressed in the duodenal brush border, we hypothesized that its extreme alkaline pH optimum (∼pH 8-9) combined with its ability to hydrolyse regulatory purines such as ATP was part of an ecto-purinergic signalling system, consisting also of brush border P2Y receptors and cystic fibrosis transmembrane regulator-mediated HCO₃⁻ secretion. Extracellular ATP increases the rate of HCO₃⁻ secretion through this purinergic system. At high surface pH (pH(s)), AP activity is increased, which then increases the rate of ATP hydrolysis, decreasing surface ATP concentration ([ATP](s)), with a resultant decrease in the rate of HCO₃⁻ secretion, which subsequently decreases pH(s) . This feedback loop is thus hypothesized to regulate pH(s) over the duodenal mucosa, and in several other HCO₃⁻ secretory organs. As AP activity is directly related to pH(s) , and as AP hydrolyses ATP, [ATP](s) and pH(s) are co-regulated. As many essential tissue functions such as ciliary motility and lipid uptake are dependent on [ATP](s) , dysregulation of pH(s) and [ATP](s) may help explain the tissue dysfunction characteristic of diseases such as cystic fibrosis.