Differential effects of apical and basolateral uridine triphosphate on intestinal epithelial chloride secretion

Our goal was to examine the sidedness of effects of the purinergic agonist, uridine 5'-triphosphate (UTP), on Cl(-) secretion in intestinal epithelial cells. We hypothesized that UTP might exert both stimulatory and inhibitory effects. All studies were conducted with T84 intestinal epithelial cells. UTP induced Cl(-) secretion in a concentration-dependent fashion. Responses to serosally added UTP were smaller and more transient than those evoked by mucosal addition, but there was no evidence that mucosal responses involved cAMP-dependent mechanisms. Pretreatment with serosal UTP inhibited subsequent Ca(2+)-dependent Cl(-) secretion induced by carbachol or thapsigargin, or secretion induced by mucosal UTP, in a manner that was reversed by a tyrosine kinase inhibitor. The inhibitory effect of serosal UTP on Cl(-) secretion was not additive with that of carbachol, known to exert its inhibitory effects through the tyrosine kinase-dependent generation of inositol 3,4,5,6-tetrakisphosphate [Ins(3,4,5,6)P(4)]. Moreover, responses to both serosal and mucosal UTP were reduced by prior treatment of T84 cells with carbachol. Finally, serosal, but not mucosal, UTP evoked an increase in Ins(3,4,5,6)P(4). We conclude that different signaling mechanisms lie downstream of apical and basolateral UTP receptors in epithelial cells, at least in the intestine. These differences may be relevant to the use of UTP as a therapy in cystic fibrosis.