Inositol phosphate signalling

Inositol monophosphatase (IMP) is the best known member of a super-family of structurally related PMEs that can hydrolyze all substrates with sugar phosphate backbones (Figure 1.3). Biochemical and structural studies of a number of family members, including IMP, inositol polyphosphatase (IPP), fructose 1,6-bisphosphatase and the rat 3'-phosphoadenosine 5'-phosphate PAP phosphatase (RnPIP), have found that this enzyme family contains a common amino acid sequence motif which constitutes a lithium-sensitive magnesium ion binding site.20 The magnesium ion is not required for direct hydrolysis of the phosphodiester bond, but is required for binding the cleaved product and phosphate. Lithium functions to trap the cleaved product in the active site, resulting in the uncompetitive inhibition of enzyme activity.

Inhibition of IMP reduces the cellular concentration of myo-inositol (Figures 1.4 and 1.5), which is required for the production of a spectrum of inositol phosphate-based soluble compounds and membrane lipids. The most studied of these is Ins(1,4,5)P3 or InsP3, an intracellular signal molecule that binds to receptors on the endoplasmic reticulum to release calcium, which in turn elicits a range of cell responses, including activation of protein kinases such as PKC. Lithium treatment would also be expected to affect other compounds, such as Ins(1,3,4,5)P4 and InsP6, which have signalling functions; PIP2, which is hydro-lyzed by phospholipase C to produce InsP3 and diacyl glycerol (DAG), and a variety of phosphatidylinositides phosphorylated at the 3' carbon, which form membrane-binding sites for proteins such as PKB.

Valuable insights regarding the mechanism of action of lithium have been gained using a single-celled eukaryotic amoeba, Dictyostelium discoideum.18,36

Figure 1.3 Structure of the sugar myo-inositol and its most well-known signalling derivative, inositol 1,4,5-trisphosphate (Ins(1,4,5)P3 or InsP3). Carbon atoms are numbered as indicated, showing the phosphorylation ('P') at carbons 1,4 and 5

Figure 1.4 The role of lithium in the inhibition of inositol phosphate signalling. Lithium inhibits two enzymes in the phosphomonoesterase family - IMP and IPP. These enzymes enable the recycling of (myo-) inositol to produce phosphatidylinositol bisphosphate (PIP2). PIP2 is hydrolyzed on the cell membrane by phospholipase C (PLC) to produce DAG and inositol 1,4,5-trisphosphate (InsP3). InsP3 functions to release calcium from the endoplasmic reticulum. The signalling properties of InsP3 are terminated by its hydrolysis to InsP2. The 'inositol depletion' theory of BD treatment proposes that the therapeutic effect of lithium is to block inositol recycling via IMP/IPP inhibition, and thus reduce inositol levels in the cell. This would result in the attenuation of an over-stimulated InsP3 signalling pathway. Prolyl oligopeptidase regulates the breakdown of higher-order inositol phosphates (inositol pentakisphosphate and hexakisphosphate, InsP5 and InsP6) to InsP3 via modulating the activity of multiple inositol polyphosphate phosphatase (MIPP). The de novo biosynthesis of inositol, from glucose-6-phosphate, catalyzed by Inositol synthase (Ino-1), is also blocked by lithium through IMP inhibition. Inositol uptake may also provide a source of inositol via a sodium myo-inositol transporter (SMIT)

Figure 1.4 The role of lithium in the inhibition of inositol phosphate signalling. Lithium inhibits two enzymes in the phosphomonoesterase family - IMP and IPP. These enzymes enable the recycling of (myo-) inositol to produce phosphatidylinositol bisphosphate (PIP2). PIP2 is hydrolyzed on the cell membrane by phospholipase C (PLC) to produce DAG and inositol 1,4,5-trisphosphate (InsP3). InsP3 functions to release calcium from the endoplasmic reticulum. The signalling properties of InsP3 are terminated by its hydrolysis to InsP2. The 'inositol depletion' theory of BD treatment proposes that the therapeutic effect of lithium is to block inositol recycling via IMP/IPP inhibition, and thus reduce inositol levels in the cell. This would result in the attenuation of an over-stimulated InsP3 signalling pathway. Prolyl oligopeptidase regulates the breakdown of higher-order inositol phosphates (inositol pentakisphosphate and hexakisphosphate, InsP5 and InsP6) to InsP3 via modulating the activity of multiple inositol polyphosphate phosphatase (MIPP). The de novo biosynthesis of inositol, from glucose-6-phosphate, catalyzed by Inositol synthase (Ino-1), is also blocked by lithium through IMP inhibition. Inositol uptake may also provide a source of inositol via a sodium myo-inositol transporter (SMIT)

This research has identified mutants resistant to the effect of lithium - and one of these mutants, lisA, has an elevated InsP3 concentration due to the up-regulation of multiple inositol polyphosphate phosphatase (MIPP) activity (Figure 1.4). This enzyme generates InsP3 from an unconventional route, by the dephosphorylation of InsP5 6. The lisA gene encodes prolyl oligopeptidase (PO), a cytosolic enzyme characterized by its ability to cleave peptides of less than 3 kDa at a proline residue. PO activity is important for brain function as its inhibitors enhance memory; lithium has the opposite effect on memory. This inverse relationship between PO activity and InsP3 concentration has been demonstrated in mammalian neurons and cell lines derived from astrocytes, ancillary cells associated with brain neurons. Of particular interest is the association of abnormal PO activity with mood disorders and a number of other mental illnesses.37 39

Figure 1.5 Schematic graphs showing different modes of enzyme inhibition. The uncompetitive nature of lithium's inhibition of IMP means that enzyme activity decreases with increasing lithium concentration, but at high substrate concentrations (low x-axis values) the inhibitory effect of lithium is stronger than that found in other forms of enzyme inhibition (competitive and non-competitive)42

Figure 1.5 Schematic graphs showing different modes of enzyme inhibition. The uncompetitive nature of lithium's inhibition of IMP means that enzyme activity decreases with increasing lithium concentration, but at high substrate concentrations (low x-axis values) the inhibitory effect of lithium is stronger than that found in other forms of enzyme inhibition (competitive and non-competitive)42

In addition to lithium's effect on inositol phosphate metabolism, some PMEs, such as RnPIP and the Saccharomyces cerevisiae protein Hal2, can also efficiently dephosphorylate di-phosphonucleotide substrates, such as 3'-phosphoadenosine 5'-phosphate (PAP) and inositol 1,4-bisphosphate. In many cases the PAP phosphatase activity is the dominant enzyme activity. PAP phosphatase catalyzes the hydrolysis of PAP to form adenosine monophosphate (AMP). Lithium inhibition, therefore, may lead to increased PAP levels, which is a potent inhibitor of enzymes that utilize PAPs, such as the sulphotransferases. Loss of PAP phosphatase genes in yeasts causes dependence on exogenous sulphur and methioinine and inhibits RNA processing. This pathway is involved in the salt tolerance response in plants and fungi. It is not yet clear whether blocking PAP phosphatase contributes to the therapeutic action of lithium in the treatment of BD.

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