Loss of a prolyl oligopeptidase confers resistance to lithium by elevation of inositol (1,4,5) trisphosphate

Abstract

The therapeutic properties of lithium ions (Li+) are well known; however, the mechanism of their action remains unclear. To investigate this problem, we have isolated Li+-resistant mutants from Dictyostelium. Here, we describe the analysis of one of these mutants. This mutant lacks the Dictyostelium prolyl oligopeptidase gene (dpoA). We have examined the relationship between dpoA and the two major biological targets of lithium: glycogen synthase kinase 3 (GSK-3) and signal transduction via inositol (1,4,5) trisphosphate (IP3). We find no evidence for an interaction with GSK-3, but instead find that loss of dpoA causes an increased concentration of IP3. The same increase in IP3 is induced in wild-type cells by a prolyl oligopeptidase (POase) inhibitor. IP3 concentrations increase via an unconventional mechanism that involves enhanced dephosphorylation of inositol (1,3,4,5,6) pentakisphosphate. Loss of DpoA activity therefore counteracts the reduction in IP3 concentration caused by Li+ treatment. Abnormal POase activity is associated with both unipolar and bipolar depression; however, the function of POase in these conditions is unclear. Our results offer a novel mechanism that links POase activity to IP3 signalling and provides further clues for the action of Li+ in the treatment of depression.

Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

“…This includes inositol monophosphatase (Shamir et al 1998), diphosphoinositol polyphosphate phosphohydrolase II (Hua et al 2001), sodium/myo-inositol cotransporter (Lubrich and van Calker 1999), aldolase A (Hua et al 2000) and C isozymes (Hua and Li, unpublished), prolyl oligopeptidase (Williams et al 1999), and CD151 (present study). Such a cluster of changes is unlikely a chance event.…”

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

“…16 In Dictyostelium, both Li þ and VPA reduce total Ins(1,4,5)P 3 concentrations and cause similar changes in cell chemotaxis. 15,17 Here, combining Li þ and VPA at subthreshold concentrations leads to an enhanced effect, suggesting that each drug works within the same signal transduction pathway, but on different components (Figure 1). In cytosolic extracts from yeast and the human brain, VPA inhibits inositol synthase/Ino1 activity and hence targets inositol synthesis.…”

“…Ablation of the gene encoding the enzyme prolyl oligopeptidase (PO) generated cells with reduced sensitivity to Li þ . 17 When tested, these mutants were discovered to be crossresistant to VPA. These PO mutants have elevated basal concentrations of Ins(1,4,5)P 3 , suggesting that they have upregulated their InsP biosynthetic pathway.…”

A 914-bp promoter is sufficient to reproduce the endogenous prolyl oligopeptidase gene localization in the mouse placenta if not subject to position effect

“…POP is known to be a multifunctional protein and has been reported to play some roles in the degradation of hormones and neuropeptides (Mentlein, 1988;Wilk, 1983), learning and memory (Miura et al, 1997;Shishido et al, 1998;Toide et al, 1995;Yoshimoto et al, 1987), cell signaling (Williams et al, 1999), cell differentiation (Hannula et al, 2011;Ohtsuki et al, 1994), sperm motility (Kimura et al, 2002;Yoshida et al, 1999), obesity Warden et al, 2009), and so on. POP has also attracted attention as a therapeutic target because it is possibly involved in several diseases such as bipolar disorder, Alzheimer's disease, and cancer (García-Horsman et al, 2007;Myöhänen et al, 2009;Williams, 2004).…”