The role of epithelial P2Y2 and P2Y4 receptors in the regulation of intestinal chloride secretion.

UTP-induced chloride secretion by the intestinal mucosa mounted in Ussing chambers was assessed by measurement of the short-circuit current (I(sc)) in the presence of phloridzin in the case of jejunum or amiloride in the case of colon to eliminate any contribution of electrogenic Na(+) movement to the net ionic transport. Since we have previously demonstrated the absence of chloride-secretory response to apical UTP in the jejunum from P2Y(4)-null mice, in the present study we studied the response to basolateral UTP in the jejunum and to either apical or basolateral UTP in the colon, in both P2Y(2)- and P2Y(4)-deficient mice. In the jejunum, the chloride-secretory response to basolateral UTP was partially reduced in both P2Y(2)- (40%) and P2Y(4)- (60%) null mice. In the colon, both apical or basolateral UTP increased the I(sc). That response was abolished in a chloride-free medium. The colonic chloride-secretory response to either basolateral or apical UTP was abolished in P2Y(4)-deficient mice, but not significantly affected in P2Y(2)-deficient mice. The chloride-secretory response to forskolin was potentiated by prior basolateral addition of UTP and this potentiation was abolished in P2Y(4)-null mice. The jejunum of mice homozygous for the DeltaF508 mutation of cystic fibrosis transmembrane conductance regulator was responsive to UTP, but the magnitude of that response was smaller than in the wild-type littermates. In conclusion, the P2Y(4) receptor fully mediates the chloride-secretory response to UTP in both small and large intestines, except at the basolateral side of the jejunum, where both P2Y(2) and P2Y(4) receptors are involved.