Ins(3,4,5,6)P-4 specifically inhibits a receptor-mediated Ca2+-dependent Cl- current in CFPAC-1 cells

We have examined the role of inositol 3,4,5,6-tetrakisphosphate [Ins(3,4,5,6)P-4] in the control of Cl- current in CFPAC-1 cells. Intracellular Ins(3,4,5,6)P-4 had no effect on basal current, but it produced a five- to sevenfold reduction in the Cl- current stimulated by either 2 mu M extracellular ATP or by 1 mu M extracellular thapsigargin. The half-maximally effective dose of Ins(3,4,5,6)P-4 was 2.9 mu M, and 4 mu M blocked >80% of the ATP-activated current. In contrast, 10 mu M Ins(1,4,5,6)P-4, Ins(1,3,4,5)P-4, or Ins(1,3,4,6)P-4 enhanced rather than inhibited the ATP-activated Cl- current, although Ins(1,4,5,6)P-4 only acted transiently. These stimulatory effects were Ca2+ dependent and largely inhibited by coapplication of equimolar Ins(3,4,5,6)P-4. Inositol 1,3,4,5,6-pentakisphosphate, the precursor of Ins(3,4,5,6)P-4, did not affect Cl- current. These data consolidate and extend the hypothesis that Ins(3,4,5,6)P-4 is an important intracellular regulator of Cl- current in epithelial cells.