Ins(3,4,5,6)P₄ 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)P₄] in the control of Cl current in CFPAC-1 cells. Intracellular Ins(3,4,5,6)P₄ had no effect on basal current, but it produced a five- to sevenfold reduction in the Cl current stimulated by either 2 μM extracellular ATP or by 1 μM extracellular thapsigargin. The half-maximally effective dose of Ins(3,4,5,6)P₄ was 2.9 μM, and 4 μM blocked >80% of the ATP-activated current. In contrast, 10 μM Ins(1,4,5,6)P₄, Ins(1,3,4,5)P₄, or Ins(1,3,4,6)P₄ enhanced rather than inhibited the ATP-activated Cl^- current, although Ins(1,4,5,6)P₄ only acted transiently. These stimulatory effects were Ca²⁺ dependent and largely inhibited by coapplication of equimolar Ins(3,4,5,6)P₄. Inositol 1,3,4,5,6-pentakisphosphate, the precursor of Ins(3,4,5,6)P₄, did not affect Cl^- current. These data consolidate and extend the hypothesis that Ins(3,4,5,6)P₄ is an important intracellular regulator of Cl^- current in epithelial cells.