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 phosphatidylinositol 3-kinase (PI 3-kinase) alters Na(+) transport in unstimulated and aldosterone-prestimulated A6 epithelia. From baseline Na(+) transport rates (I(Na)) of 4.0 +/- 0.1 (unstimulated) and 9.1 +/- 0.9 microA/cm(2) (aldosterone), 10 microM LY-294002 caused, following a relatively small initial increase of transport, a completely reversible inhibition of transport within 90 min to 33 +/- 6% and 38 +/- 2% of respective baseline values. Initial increases of transport could be attributed to increases of channel open probability (P(o)) within 5 min to 143 +/- 17% (unstimulated) and 142 +/- 10% of control (aldosterone) from baseline P(o) averaging near 0.5. Inhibition of transport was due to much slower decreases of functional channel densities (N(T)) to 28 +/- 4% (unstimulated) and 35 +/- 3% (aldosterone) of control at 90 min. LY-294002 (50 microM) caused larger but completely reversible increases of P(o) (215 +/- 38% of control at 5 min) and more rapid but only slightly larger decreases 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-kinase 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.
Păunescu
T G
TG
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Blazer-Yost
B L
BL
Vlahos
C J
CJ
Helman
S I
SI
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology*; D004553:Electric Conductivity; D017097:Electric Impedance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D053503:Epithelial Sodium Channels; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007686:Kidney Tubules, Distal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011336:Probability; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism; D013997:Time Factors; D014982:Xenopus laevis
D000450:Aldosterone; D002867:Chromones; D004791:Enzyme Inhibitors; D053503:Epithelial Sodium Channels; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012964:Sodium; D015222:Sodium Channels; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one