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  • Review Article
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Back in the water: the return of the inositol phosphates

Key Points

  • There has been great progress recently in our knowledge of potential functions for inositol phosphates (other than inositol-1,4,5-trisphosphate Ins(1,4,5)P3), as well as in our understanding of the enzymes that metabolize them, although we still remain uncertain about many of the details of the metabolic pathways.

  • Inositol-1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4) has several functions in animal cells, where it is synthesized from Ins(1,4,5)P3 by a family of 3-kinases that have evolved quite recently in animals.

  • Inositol-3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P4) functions as a negative regulator of chloride efflux in epithelial cells. Although the molecular details are not all clear, the implications for cystic fibrosis have a possible clinical relevance.

  • Inositol-1,4,5,6-tetrakisphosphate (Ins(1,4,5,6)P4) might also have a physiological role, indicated by its unusual metabolism, but we do not yet know what that role is.

  • Inositol-1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P5) is a metabolic 'hub' in inositol phosphates, but has no clearly defined function other than its suggested role as a modulator of haemoglobin in erythrocytes of a few animal species, a role that might be more complex than has previously been suspected.

  • Inositol hexakisphosphate (InsP6) has been suggested to fulfill many functions, and recently there have been several new possibilities proposed. These include K+ channel regulation in plant guard cells, controlling messenger RNA transport from the nucleus, regulating DNA repair and a role in endocytosis (possibly involving an InsP6-regulated protein kinase).

  • InsP7 and InsP8 are the newest members of the physiological inositol phosphate repertoire, which might function as drivers of membrane–protein interactions by acting as a localized energy source.

Abstract

Following the discovery of inositol-1,4,5-trisphosphate as a second messenger, many other inositol phosphates were discovered in quick succession, with some understanding of their synthesis pathways and a few guesses at their possible functions. But then it all seemed to go comparatively quiet, with an explosion of interest in the inositol lipids. Now the water-soluble phase is once again becoming a focus of interest. Old and new data point to a new vista of inositol phosphates, with functions in many diverse aspects of cell biology, such as ion-channel physiology, membrane dynamics and nuclear signalling.

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Figure 1: Pathways of metabolism of inositol phosphates.
Figure 2: Consequences of inositol-1,3,4,5-tetrakisphosphate generation.

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Acknowledgements

We are grateful to our many colleagues for helpful discussions and supply of pre-prints, but in particular we would like to thank S. Shears, A. Saiardi, B. Michell, P. Hawkins and G. Ihrke. R.F.I. is supported by the Royal Society and M.J.S. by the Wellcome Trust. The poem by O. Nash is reproduced with the kind permission of L. Nash Smith and I. Nash Eberstadt.

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The turtle lives 'twixt plated decks Which practically conceal its sex. I think it clever of the turtle In such a fix to be so fertile. Ogden Nash (1902–1971)

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DATABASE LINKS

Src

Ins (1,4,5)P3 3-kinase

CaM

CaMKII

phospholipase C

Ins(1,4,5)P3 receptors

GAP1m

CLCA1

Ins(3,4,5,6)P4 1-kinase

SopB

protein kinase C

synaptotagmins

pacsin

phosphoinositide-specific phospholipase C

DNA-dependent protein kinase

AP-180

AP-2

Arg82

Arg80

Mcm1

Arg81

MIPP

GAP1IP4BP

FURTHER INFORMATION

Shears' lab

Pirarucu

Another view of inositol phosphate metabolism

Sources of inositol phosphates

IUBMB nomenclature of inositides

LINKS

Sources of inositol phosphates

Glossary

VMAX (Vmax).

The maximum velocity (that is, the rate) at which an enzyme can catalyse a reaction. This occurs when the substrate is at a concentration that saturates the enzyme, and the concentration of the enzymatic product is low.

COINCIDENCE DETECTION

The process whereby a cell responds differently to a signal if another signal is received simultaneously (or just before). This is particularly important in the brain, where different spatial, temporal and chemical inputs to a neuron can alter the neuron's output.

LTP

Long-term potentiation is a specific example of coincidence detection, whereby the high frequency stimulation of a neuron increases the magnitude of subsequent responses, an effect that can last for days. LTP is believed to underlie some kinds of learning and memory.

INS(1,4,5)P3 RECEPTORS

Ca2+ channels located on the endoplasmic reticulum which, when Ins(1,4,5)P3 binds to them, open to release stored Ca2+. There are three subtypes (I, II and III); all have similar structures and functions.

STORE-OPERATED CA2+ ENTRY

The activation of a Ca2+ channel in the plasma membrane in response to the depletion of Ca2+ levels in the endoplasmic reticulum (ER). Decreases in the levels of stored Ca2+ inside the ER somehow signal to the plasma membrane channels (store-operated calcium channels, or SOCs).

L-1210 CELLS

A mouse lymphoma cell line that grows readily in suspension, a property useful for studying Ca2+ homeostasis in permeabilized cells.

T-84 CELLS

A colonic epithelial cell line.

PATCH-CLAMP

The technique of attaching a pipette to the outside of a cell, and either pulling the small piece of membrane captured within it off the cell ('excised patch') or rupturing this piece, thus making the interior of the cell continuous with the inside of the pipette ('whole cell patch').

PI3K AND PTDINS(3,4,5)P3

The phosphatidylinositol 3-kinases are a family of enzymes that phosphorylate the 3-position on inositol lipids. The type I varieties are the most relevant for signal transduction because they are receptor-regulated; they prefer phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) as a substrate and thus make the second messenger PtdIns(3,4,5)P3.

GUARD CELLS

The cells found on the underside of plant leaves, which pair up to form stomata, or leaf pores. Guard cells control the size of the stomata, and thus in turn regulate gas exchange in the leaf.

ABSCISIC ACID

A plant hormone originally discovered (and named) for its ability to regulate leaf detachment; also a key regulator of guard cell shape (and thus gas exchange) in the leaf.

SYNAPTOTAGMINS

A group of Ca2+-binding proteins that are generally understood to be involved with the secretion of granules and vesicles, especially in the nervous system.

AP-2 AND AP-180

Two members of a family of so-called 'clathrin adaptor proteins', which facilitate the early stages of endocytic vesicle formation through their ability to bind clathrin coats.

ARRESTIN

Protein that, when phosphorylated, associates with G-protein-coupled receptors, thereby inhibiting the receptors' actions.

MADS BOX

A superfamily of transcription factors (including Mcm1, agamous, deficiens and serum response factor), which bind DNA and control a plethora of cellular functions.

NUDT DOMAIN

Nudix-type domain, previously known as a MutT domain. Discovered in a group of enzymes that protect cells from threats such as oxygen radicals.

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Irvine, R., Schell, M. Back in the water: the return of the inositol phosphates. Nat Rev Mol Cell Biol 2, 327–338 (2001). https://doi.org/10.1038/35073015

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