LY-294002-inhibitable PI 3-kinase and regulation of baseline rates of Na+ transport in A6 epithelia

Blocker-induced noise analysis of epithelial Na+ channels (ENaCs) was used to investigate how inhibition of an LY-294002-sensitive phosphatidylinosito l 3-kinase (PI 3-kinase) alters Na+ transport in unstimulated and aldostero ne-prestimulated A6 epithelia. From baseline Na+ transport rates (I-Na) of 4.0 +/- 0.1 (unstimulated) and 9.1 +/- 0.9 mu A/cm(2) (aldosterone), 10 mu M LY-294002 caused, following a relatively small initial increase of transp ort, a completely reversible inhibition of transport within 90 min to 33 +/ - 6% and 38 +/- 2% of respective baseline values. Initial increases of tran sport could be attributed to increases of channel open probability (P-o) wi thin 5 min to 143 +/- 17% (unstimulated) and 142 +/- 10% of control (aldost erone) from baseline P-o averaging near 0.5. Inhibition of transport was du e to much slower decreases of functional channel densities (N-T) to 28 +/- 4% (unstimulated) and 35 +/- 3% (aldosterone) of control at 90 min. LY-2940 02 (50 mu M) caused larger but completely reversible increases of P-o (215 +/- 38% of control at 5 min) and more rapid but only slightly larger decrea ses of N-T. Basolateral exposure to LY-294002 induced no detectable effect on transport, P-o or N-T. We conclude that an LY-294002-sensitive PI 3-kina se plays an important role in regulation of transport by modulating N-T and P-o of ENaCs, but only when presented to apical surfaces of the cells.