Regulation of Ins(3,4,5,6)P4 signaling by a reversible kinase/phosphatase

Regulation of Cl- channel conductance by Ins(3,4,5,6)P-4 provides receptor-dependent control over salt and fluid secretion [1], cell volume homeostasis [2], and electrical excitability of neurones and smooth muscle [3]. Ignorance of how Ins(3,4,5,6)P4 is synthesized has long hindered our understanding of this signaling pathway. We now show Ins(3,4,5,6)P4 synthesis by Ins(1,3,4,5,6)P,5 1-phosphatase activity by an enzyme previously characterized [4] as an Ins(3,4,5,6)P-4 1-kinase. Rationalization of these phenomena with a ligand binding model unveils Ins(1,3,4)P-3 as not simply an alternative kinase substrate [4, 5], but also an activator of Ins(1,3,4,5,6)P-5 I-phosphatase. Stable overexpression of the enzyme in epithelial monolayers verifies its physiological role in elevating Ins(3,4,5,6)P4 levels and inhibiting secretion. It is exceptional for a single enzyme to catalyze two opposing signaling reactions (1-kinase/1-phosphatase) under physiological conditions. Reciprocal coordination of these opposing reactions offers an alternative to general doctrine that intracellular signals are regulated by integrating multiple, distinct phosphatases and kinases [6].