Extracellular ATP regulates transcervical permeability by modulating two distinct paracellular pathways.

Extracellular ATP stimulates a biphasic change in transepithelial electrical resistance (RTE) across cultures of human cervical epithelial cells: an acute decrease (phase I), followed by a delayed increase in resistance (phase II). The objective of this study was to determine the contributions of changes in the lateral intercellular space resistance (RLIS) and the tight junctional resistance (RTJ) to the changes in RTE. Phase I and phase II effects were uncoupled by treatment with 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA)-acetoxymethyl ester, which blocks the ATP-induced increases in cytosolic Ca2+ and abolishes phase I. BAPTA-loaded cells differed from control cells in that 1) phase I began when ATP was added, in contrast to a delay of 1.5-3.5 min in phase II, 2) phase I decreases in RLIS followed a simple exponential pattern, in contrast to the complex kinetics of phase II, and 3) the magnitude of phase II varied between 20 and 100% for increases of RTJ in day 2-6 cultures; the phase I decrease of 50% in RLIS was unrelated to different experimental conditions. These results indicate that phase I and phase II are induced simultaneously and independently by ATP, and they contribute to the total changes in RTE. We conclude that ATP regulation of RLIS and RTJ may be important mechanisms of modulating cervical mucus production in vivo.