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.