Defining signal transduction by inositol phosphates

Abstract

Ins(1,4,5)P(3) is a classical intracellular messenger: stimulus-dependent changes in its levels elicits biological effects through its release of intracellular Ca(2+) stores. The Ins(1,4,5)P(3) response is "switched off" by its metabolism to a range of additional inositol phosphates. These metabolites have themselves come to be collectively described as a signaling "family". The validity of that latter definition is critically examined in this review. That is, we assess the strength of the hypothesis that Ins(1,4,5)P(3) metabolites are themselves "classical" signals. Put another way, what is the evidence that the biological function of a particular inositol phosphate depends upon stimulus dependent changes in its levels? In this assessment, examples of an inositol phosphate acting as a cofactor (i.e. its function is not stimulus-dependent) do not satisfy our signaling criteria. We conclude that Ins(3,4,5,6)P(4) is, to date, the only Ins(1,4,5)P(3) metabolite that has been validated to act as a second messenger.

Fig. 13.1

Inositol phosphate metabolism. The figure shows the pathway of Ins(1,4,5)P₃ metabolism. The numbers in circles indicate the different enzymes that are involved: 1, IPK2/IPMK; 2, Ins(1,4,5)P₃ 3-kinases; 3, Ins(1,4,5)P₃/ Ins(1,3,4,5)P₄ 5-phopshatase; 4, ITPK1; 5, PTEN; 6, IP5K. There is a candidate for the question mark—MIPP—but it is uncertain how that enzyme can access its substrate (see text for details). The inositol pyrophosphates are not shown in this figure (they are the subject of a separate chapter (Saiardi 2011)). The enzymes that dephosphorylate Ins(1,4,5)P₃ and Ins(1,3,4)P₃ to inositol are not shown, as this review is only concerned with metabolites that have received attention as being cellular signals. Note that the positional specificity of IPK2/IPMK shows phylogenetic variation. In yeasts, Ins(1,4,5)P₃ is phosphorylated primarily to Ins(1,4,5,6)P₄, in mammals the product is predominantly Ins(1,3,4,5)P₄, and the enzyme in flies produces roughly equal quantities of both InsP₄ isomers

Fig. 13.2

The phosphotransferase activity of ITPK1. The figure shows the phosphotransferase activity that is catalyzed by ITPK1. The phosphate group that is transferred between from Ins(1,3,4,5,6)P₅ to Ins(1,3,4)P₃ is highlighted in by the grey circle