A biologic function for an ''orphan'' messenger: D-myo-inositol 3,4,5,6-tetrakisphosphate selectively blocks epithelial calcium-activated chloride channels

Inositol phosphates are a family of water-soluble intracellular signaling molecules derived from membrane inositol phospholipids, They undergo a variety of complex interconversion pathways, and their levels are dynamically regulated within the cytosol in response to a variety of agonists, Relatively little is known about the biological function of most members of this family, with the exception of inositol 1,4,5-trisphosphate. Specifically, the biological functions of inositol tetrakisphosphates are Largely obscure. In this paper, we report that D-myo-inositol 3,4,5,6-tetrakisphosphate (D-Ins(3,4,5,6)P-4) has a direct biphasic (activation/inhibition) effect on an epithelial Ca2+-activated chloride channel. The effect of D-Ins(3,4,5,6)P-4 is not mimicked by other inositol tetrakisphosphate isomers, is dependent on the prevailing calcium concentration, and is influenced when channels are phosphorylated by calmodulin kinase II. The predominant effect of D-Ins(3,4,5,6)P-4 on phosphorylated channels is inhibitory at levels of intracellular calcium observed in stimulated cells, Our findings indicate the biological function of a molecule hitherto considered as an ''orphan'' messenger, They suggest that the molecular target for D-Ins(3,4,5,6)P-4 is a plasma membrane Ca2+-activated chloride channel. Regulation of this channel by D-Ins(3,4,5,6)P-4 and Ca2+ may have therapeutic implications for the disease states of both diabetic nephropathy and cystic fibrosis.