Stepwise enzymatic dephosphorylation of inositol 1,4,5-trisphosphate to inositol in liver

Abstract

Many receptors for hormones, neurotransmitters and other signals cause hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂) and effect a rise in cytosolic Ca²⁺ concentration^1–7. The inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃) liberated during PtdIns(4,5)P₂ breakdown seems to serve as a second messenger that activates the release of Ca²⁺ from a nonmitochondrial intracellular compartment^7–12. As expected if it is an important intracellular messenger, Ins(1,4,5)P₃ is relatively rapidly degraded, both within stimulated cells^13,14 and when added to homogenates of blowfly salivary gland¹⁵ or to permeabilized, but not intact, hepatocytes¹⁰. Here we report that the dephosphorylation reactions responsible for the conversion of Ins(1,4,5)P₃ to free inositol in rat liver are catalysed by two or more enzymes, and that these reactions are distributed between the plasma membrane and cytosol. The Ins(1,4,5)P₃ 5-phosphatase and inositol 1-phosphate (Ins(1)P) phosphatase of liver appear similar to enzymes described previously in erythrocytes¹⁶ and brain¹⁷.