The inositol tris/tetrakisphosphate pathway—demonstration of Ins(l,4,5)P₃ 3-kinase activity in animal tissues

Abstract

Recent advances in our understanding of the role of inositides in cell signalling have led to the central hypothesis that a receptorstimulated phosphodiesteratic hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂)^1,2 results in the formation of two second messengers, diacylglycerol³ and inositol 1,4,5-trisphosphate (Ins(l,4,5)P₃)⁴. The existence of another pathway of inositide metabolism was first suggested by the discovery that a novel inositol trisphosphate, Ins(l,3,4)P₃, is formed in stimulated tissues⁵; the metabolic kinetics of Ins(l,3,4)P₃ are entirely different from those of Ins(l,4,5)P₃ (refs 6, 7). The probable route of formation of Ins(l,3,4)P₃ was recently shown to be via a 5-dephosphorylation of inositol 1,3,4,5-tetrakisphosphate (Ins(l,3,4,5)P₄), a compound which is rapidly formed on muscarinic stimulation of brain slices, and which can be readily converted to Ins(l,3,4)P₃ by a 5-phosphatase in red blood cell membranes⁸. However, the source of Ins(l,3,4,5)P₄ is unclear, and an attempt to detect a possible parent lipid, phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P₃), was unsuccessful⁸. The recent discovery that the higher phosphorylated forms of inositol (InsP₅ and InsP₆) also exist in animal cells⁹ suggested that inositol phosphate kinases might not be confined to plant and avian tissues, and here we show that a variety of animal tissues contain an active and specific Ins(l,4,5)P₃ 3-kinase. We therefore suggest that an inositol tris/tetrakisphosphate pathway exists as an alternative route to the dephosphorylation^10,11 of Ins(l,4,5)P₃. The function of this novel pathway is unknown.