PIP2 and bipolar disorder


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(Updated 8/25/04)

[PIP2 is known to inhibit the product of a gene that has been shown to be linked to bipolar disorder in some individuals. Click here to learn more.]

Soares JC, Mallinger AG, Dippold CS, Forster Wells K, Frank E, Kupfer DJ.
Effects of lithium on platelet membrane phosphoinositides in bipolar disorder patients: a pilot study.
Psychopharmacology (Berl). 2000 Mar;149(1):12-6.
"RATIONALE: In vitro and in vivo animal studies suggest that the intracellular phosphatidylinositol (PI) pathway is an important target for the effects of lithium. OBJECTIVES: We conducted a preliminary study to examine the in vivo effects of lithium treatment on platelet membrane phosphoinositides in bipolar disorder subjects, in an attempt to examine further the hypothesis that lithium has significant in vivo effects on the PI pathway in these patients. METHODS: We quantitated PI, phosphatidylinositol-4-phosphate (PIP), and phosphatidylinositol-4,5-bisphosphate (PIP2) in platelet membranes of seven subjects (five male, two female; mean age= 27.9+/-5.7 years), initially while they were unmedicated, and a second time after at least 21 days of lithium treatment (mean+/-SD=28.7+/-7.1 days). RESULTS: The mean+/-SD values for PI were 5.63+/-2.25% and 5.21+/-1.06%; for PIP 0.68+/-0.20% and 0.55+/-0.11%; and for PIP2 0.60+/-0.21% and 0.38+/-0.15%, before and after lithium treatment, respectively. The decrease in PIP2 values after lithium treatment was statistically significant (Wilcoxon signed ranks test, Z=-2.37, P=0.02). CONCLUSION: This longitudinal study suggests that therapeutic doses of lithium significantly decrease platelet membrane PIP2 levels in vivo in bipolar disorder subjects, which may be related to lithium's mechanism of action in bipolar disorder." [Abstract]

Soares JC, Mallinger AG, Dippold CS, Frank E, Kupfer DJ.
Platelet membrane phospholipids in euthymic bipolar disorder patients: are they affected by lithium treatment?
Biol Psychiatry. 1999 Feb 15;45(4):453-7.
"BACKGROUND: Abnormalities in cell membrane processes and intracellular signal transduction pathways may be implicated in the pathophysiology of bipolar disorder. In this study, we attempted to investigate, in euthymic bipolar patients: 1) in vivo signal transduction abnormalities of the phosphatidylinositol pathway in platelets; and 2) possible in vivo effects of lithium treatment on platelet membrane phospholipids. METHODS: We determined the relative absorbances of eight individual classes of platelet membrane phospholipids, using two-dimensional thin-layer chromatography in high-performance plates, followed by scanning laser densitometry, in a group of 10 lithium-treated euthymic bipolar patients and 11 normal controls. RESULTS: The mean relative absorbance of phosphatidyl-inositol-4,5-bisphosphate (PIP2) was lower in the patient group (0.29 +/- 0.08% vs. 0.39 +/- 0.12%; t = 2.35, df = 19, p = .03); no significant differences between patients and controls were found for the other phospholipids. CONCLUSIONS: This study provides in vivo evidence that bipolar patients on lithium treatment exhibit a decreased relative amount of PIP2 in the platelet cell membranes compared to normal controls." [Abstract]

Soares JC, Chen G, Dippold CS, Wells KF, Frank E, Kupfer DJ, Manji HK, Mallinger AG.
Concurrent measures of protein kinase C and phosphoinositides in lithium-treated bipolar patients and healthy individuals: a preliminary study.
Psychiatry Res. 2000 Aug 21;95(2):109-18.
"This study examined the hypothesis that lithium inhibits the PI signaling pathway in humans during in vivo administration by concurrently measuring PKC isozymes and platelet membrane phosphoinositides in lithium-treated patients and healthy individuals. The platelet membrane and cytosolic levels of PKC alpha, beta I, beta II, delta, and epsilon were measured using Western blotting. The relative platelet membrane contents of phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PIP), and phosphatidylinositol-4,5-bisphosphate (PIP(2)) were measured with two-dimensional thin-layer chromatography. Nine euthymic lithium-treated bipolar subjects and 11 healthy control subjects were studied. Compared to control subjects, lithium-treated bipolar patients had significantly lower levels of cytosolic PKC alpha isozyme (t-test=-3.24, d.f.=17, P=0.01) and PIP(2) platelet membrane levels (t-test=-2.51, d.f.=18, P=0.02), and a trend toward reduced levels of cytosolic PKC beta II isozyme (t=-2.17, d.f.=17, P=0.05). There was no significant correlation between PIP(2) and any of the PKC isozymes. These preliminary findings suggest that chronic lithium treatment may decrease the levels of both cytosolic PKC alpha isozyme and membrane PIP(2) in platelets of bipolar disorder patients." [Abstract]

Vadnal RE, Bazan NG.
Electroconvulsive shock stimulates polyphosphoinositide degradation and inositol trisphosphate accumulation in rat cerebrum: lithium pretreatment does not potentiate these changes.
Neurosci Lett. 1987 Sep 11;80(1):75-9.
"Using an in vivo model, we explored the acute effects of electroconvulsive shock (ECS) and lithium on rat cerebral polyphosphoinositides and inositol phosphates. ECS was shown to increase the [3H]inositol trisphosphate ([3H]IP3) by 75%, decrease the endogenous mass of phosphatidylinositol 4,5-bisphosphate (PIP2) by 23%, and enhance [3H]myo-inositol labeling into the polyphosphoinositides. In contrast, lithium pretreatment 20-24 h prior to ECS appeared to attenuate the ECS-induced [3H]IP3 increase and the decrease in mass of PIP2; [3H]inositol monophosphate ([3H]IP1) levels demonstrated no differences between the lithium ECS and lithium-alone groups. These results indicate that ECS stimulates the inositol lipid cycle in brain possibly due to neurotransmitter release. Moreover, the effects of lithium suggest other possible sites of action of this cation on inositol lipid metabolism in addition to an inhibition of inositol-1-phosphatase." [Abstract]

Gur E, Lerer B, Newman ME.
Acute or chronic lithium does not affect agonist-stimulated inositol trisphosphate formation in rat brain in vivo.
Neuroreport. 1996 Jan 31;7(2):393-6.
"Rats were given lithium either acutely by s.c. injection (4 m eq kg-1) or chronically by including 0.2% LiCl in their diet for 3 weeks. Microdialysis probes were inserted into the cortex or hippocampus, using re-usable guides, and perfused with artificial CSF. Fractions were collected beginning 18 h after the end of treatment and were analysed for inositol trisphosphate (IP3). Neither acute nor chronic treatment affected basal levels of IP3 or stimulation of IP3 formation by either carbachol or noradrenaline in the hippocampus. Similarly, neither basal nor carbachol-stimulated IP3 levels in rat cortex were affected by acute Li administration. It would appear that the reductions in these parameters previously reported by other workers using brain slices were due to inositol depletion occurring at the stage of brain slice preparation. The inositol depletion hypothesis for the mechanism of action of lithium does not therefore appear to be supported by in vivo evidence." [Abstract]

Ishima Y, Fujimagari M, Masuzawa Y, Waku K.
Inositol 1,4,5-trisphosphate accumulation in brain of lithium-treated rats.
Lipids. 1993 Jul;28(7):577-81.
"The mechanism of action of lithium as a drug for patients with affective disorders was investigated. Three-week-old male rats were orally administered 2.7 mEq Li2CO3/kg/d for 1 or 3 wk, and phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP), phosphatidylinositol 4,5-bisphosphate (PIP2), inositol phosphate (IP), inositol diphosphate (IP2) and inositol triphosphate (IP3) levels in brain were measured. The levels of IP were increased 1.7 and 2.4 times after 1 wk and 3 wk of lithium administration, respectively, while PI, PIP, PIP2, IP2 and IP3 levels were not altered. IP3 was further fractionated by high-performance liquid chromatography into I-1,3,4-P3 and I-1,4,5-P3. In the control rat brain, the relative percentages of I-1,3,4-P3 and I-1,4,5-P3 were 95.8 and 4.2, respectively. However, after 3 wk of lithium administration, the values were changed to 69.6 and 30.3%, respectively. This increase in the neurotransducer I-1,4,5-P3 in the brain may be relevant to the mechanism of action in the lithium treatment of patients with manic-depressive disorders." [Abstract]

Stopkova P, Saito T, Fann CS, Papolos DF, Vevera J, Paclt I, Zukov I, Stryjer R, Strous RD, Lachman HM.
Polymorphism screening of PIP5K2A: a candidate gene for chromosome 10p-linked psychiatric disorders.
Am J Med Genet. 2003 Nov 15;123B(1):50-8.
"Lithium is a potent noncompetitive inhibitor of inositol monophosphatases, enzymes involved in phosphoinositide (PI) and inositol phosphate metabolism. A critical component of the PI pathway is phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)), which is hydrolyzed to second messengers and has a direct role in synaptic vesicle function. Interestingly, a number of genes involved in the synthesis and dephosphorylation of PtdIns(4,5)P(2) are found in regions of the genome previously mapped in bipolar disorder (BD) including 10p12, 21q22, and 22q11, among others. Some of these regions overlap with loci mapped in schizophrenia (SZ). One gene involved in PI metabolism that maps to a region of interest is 10p12-linked PIP5K2A, a member of the phosphatidylinositol 4-phosphate 5-kinase family. Polymorphism screening revealed the existence of an imperfect CT repeat polymorphism located near the exon 9-intron 9 splice donor site. A modest difference was found in the distribution of alleles from this highly polymorphic variant when bipolar and schizophrenic subjects were compared with controls; relatively rare short repeat variants were found more commonly in patients and homozygosity for a common long repeat variant was found more commonly in controls. These data suggest that the imperfect CT repeat in PIP5K2A intron 9 should be further investigated as a possible candidate allele for 10p12-linked psychiatric disorders." [Abstract]

Soares JC, Dippold CS, Wells KF, Frank E, Kupfer DJ, Mallinger AG.
Increased platelet membrane phosphatidylinositol-4,5-bisphosphate in drug-free depressed bipolar patients.
Neurosci Lett. 2001 Feb 16;299(1-2):150-2.
"Prior investigations in bipolar disorder patients have suggested abnormalities in the cellular phosphoinositide second messenger system. This study was conducted to examine the levels of platelet membrane phosphoinositides in drug-free bipolar patients in the depressed state (n=9) and healthy controls (n=19). Bipolar patients had significantly increased levels of platelet membrane phosphatidylinositol-4,5-bisphosphate (PIP(2)) compared to healthy individuals (0.67+/-0.14 and 0.44+/-0.17%, respectively, t-test=3.71, d.f.=26, P=0.001). No significant differences in the levels of phosphatidylinositol-4-phosphate (PIP) (0.65+/-0.17 and 0.58+/-0.20%, respectively, t-test=1.02; d.f.=26; P=0.32) or phosphatidylinositol (PI) (5.92+/-1.23 and 5.56+/-1.45%, respectively, t-test=0.68; d.f.=26; P=0.51) were found. These findings provide the first demonstration of increased PIP(2) platelet levels in bipolar patients in the depressed state, and provide additional evidence that the phosphoinositide second messenger system may be a site of abnormality in bipolar disorder." [Abstract]

Soares JC, Dippold CS, Mallinger AG.
Platelet membrane phosphatidylinositol-4,5-bisphosphate alterations in bipolar disorder--evidence from a single case study.
Psychiatry Res. 1997 Mar 24;69(2-3):197-202.
"Abnormalities in the cellular phosphatidylinositol (PI) pathway have been proposed to be implicated in the pathophysiology of bipolar disorder. A platelet model was used to study phosphatidylinositol-4,5-bisphosphate (PIP2) membrane values in a bipolar disorder patient in different mood states, in a single case study. The patient was studied unmedicated, initially in the euthymic and later in the manic states, and subsequently on lithium after remission of manic symptoms. The relative percentage of PIP2 in the platelet membranes increased with cycling from the euthymic into the manic state. After lithium treatment, PIP2 decreased, and was similar to the euthymic state. This study further demonstrates the feasibility of this method, as well as its applicability to longitudinal studies in bipolar disorder, and suggests promising directions for future research in this area." [Abstract]

Brown AS, Mallinger AG, Renbaum LC.
Elevated platelet membrane phosphatidylinositol-4,5-bisphosphate in bipolar mania.
Am J Psychiatry. 1993 Aug;150(8):1252-4.
"Membrane phospholipids were measured in platelets of seven medication-free patients in the manic phase of bipolar affective disorder and seven healthy comparison subjects. The relative percentage of platelet membrane phosphatidylinositol-4,5-bisphosphate was significantly higher in the manic patients than in the comparison subjects." [Abstract]

Parthasarathy LK, Seelan RS, Wilson MA, Vadnal RE, Parthasarathy RN.
Regional changes in rat brain inositol monophosphatase 1 (IMPase 1) activity with chronic lithium treatment.
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Feb;27(1):55-60.
"Myo-inositol monophosphatase 1 (IMPase 1) is one of the targets for the mood-stabilizing action of lithium. Inhibition of IMPase is the basis for the "inositol depletion hypothesis" for the molecular action of lithium. To better understand the precise action of chronic (up to 4 weeks) lithium treatment on IMPase 1 activity, we measured IMPase 1 activity using both a colorimetric and a radiometric assay in rats (53-58 days old) fed a diet containing 0.2% lithium carbonate. Our results show that IMPase 1 activity increases substantially in the various brain regions analyzed, even doubling in some regions in the following order, after chronic treatment: hippocampus>cerebellum>striatum>cerebral cortex>brain stem. Both the qualitative and quantitative increases of IMPase 1 activity by chronic lithium treatment were substantiated by Western blot analysis of hippocampal and cerebral cortex regions. We conclude that the increased IMPase 1 activity is an adaptational response to chronic lithium treatment, and may involve direct or indirect stimulation of IMPA1 (which encodes IMPase 1) and/or turnover of the enzyme. The increased enzyme activity may alter critical neurochemical processes involving either free myo-inositol, the precursor of inositol based signaling system or other metabolic pathways, since IMPase 1 also utilizes selective sugar phosphates, such as galactose-1-phosphate, as substrates. One or more of these signal and metabolic pathways may be associated with lithium's psychotherapeutic mood-stabilizing action." [Abstract]

Sjoholt G, Ebstein RP, Lie RT, Berle J, Mallet J, Deleuze JF, Levinson DF, Laurent C, Mujahed M, Bannoura I, Murad I, Molven A, Steen VM.
Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder.
Mol Psychiatry. 2003 Dec 23 [Epub ahead of print].
"Manic-depressive (bipolar) illness is a serious psychiatric disorder with a strong genetic predisposition. The disorder is likely to be multifactorial and etiologically complex, and the causes of genetic susceptibility have been difficult to unveil. Lithium therapy is a widely used pharmacological treatment of manic-depressive illness, which both stabilizes the ongoing episodes and prevents relapses. A putative target of lithium treatment has been the inhibition of the myo-inositol monophosphatase (IMPase) enzyme, which dephosphorylates myo-inositol monophosphate in the phosphatidylinositol signaling system. Two genes encoding human IMPases have so far been isolated, namely myo-inositol monophosphatase 1 (IMPA1) on chromosome 8q21.13-21.3 and myo-inositol monophosphatase 2 (IMPA2) on chromosome 18p11.2. In the present study, we have scanned for DNA variants in the human IMPA1 and IMPA2 genes in a pilot sample of Norwegian manic-depressive patients, followed by examination of selected polymorphisms and haplotypes in a family-based bipolar sample of Palestinian Arab proband-parent trios. Intriguingly, two frequent single-nucleotide polymorphisms (-461C>T and -207T>C) in the IMPA2 promoter sequence and their corresponding haplotypes showed transmission disequilibrium in the Palestinian Arab trios. No association was found between the IMPA1 polymorphisms and bipolar disorder, neither with respect to disease susceptibility nor with variation in lithium treatment response. The association between manic-depressive illness and IMPA2 variants supports several reports on the linkage of bipolar disorder to chromosome 18p11.2, and sustains the possible role of IMPA2 as a susceptibility gene in bipolar disorder." [Abstract]

Vadnal R, Parthasarathy R.
Myo-inositol monophosphatase: diverse effects of lithium, carbamazepine, and valproate.
Neuropsychopharmacology 1995 Jul;12(4):277-85
"The therapeutic molecular sites of action for the mood-stabilizing medications are unknown. Myo-inositol monophosphatase (E.C. is a major enzyme of the inositol signaling system that has previously been shown to be inhibited by clinically relevant concentrations of lithium, implicating this enzyme as a potential therapeutic site of action in manic-depressive disorder. Inhibition of myo-inositol monophosphatase (IMPase), which converts myo-inositol monophosphates to myo-inositol, results in increased levels of myo-inositol monophosphates and decreased myo-inositol available for the resynthesis of inositol phospholipids. In addition to lithium, carbamazepine and valproate are also used medically to treat manic-depressive disorder. It is of considerable interest to determine whether inhibition of IMPase activity is a common unifying mechanism for mood-stabilizing medications. Using a partially purified myo-inositol monophosphatase preparation derived from bovine brain, we examined the effects of lithium, carbamazepine, and valproate on the IMPase reaction. These results demonstrate that (1) lithium inhibited IMPase activity in the low millimolar range, (2) carbamazepine stimulated the IMPase reaction beginning in the low-micromolar range, and (3) valproate did not demonstrate any stimulation or inhibition of IMPase. We conclude that inhibition of IMPase is not a common neurochemical mechanism for mood-stabilizing medications." [Abstract]

José M. López-Coronado, José M. Bellés, Florian Lesage, Ramón Serrano, and Pedro L. Rodríguez
A Novel Mammalian Lithium-sensitive Enzyme with a Dual Enzymatic Activity, 3'-Phosphoadenosine 5'-Phosphate Phosphatase and Inositol-polyphosphate 1-Phosphatase
J. Biol. Chem. 274: 16034-16039.
"We report the molecular cloning in Rattus norvegicus of a novel mammalian enzyme (RnPIP), which shows both 3'-phosphoadenosine 5'-phosphate (PAP) phosphatase and inositol-polyphosphate 1-phosphatase activities. This enzyme is the first PAP phosphatase characterized at the molecular level in mammals, and it represents the first member of a novel family of dual specificity enzymes. The phosphatase activity is strictly dependent on Mg2+, and it is inhibited by Ca2+ and Li+ ions. Lithium chloride inhibits the hydrolysis of both PAP and inositol-1,4-bisphosphate at submillimolar concentration; therefore, it is possible that the inhibition of the human homologue of RnPIP by lithium ions is related to the pharmacological action of lithium. We propose that the PAP phosphatase activity of RnPIP is crucial for the function of enzymes sensitive to inhibition by PAP, such as sulfotransferase and RNA processing enzymes. Finally, an unexpected connection between PAP and inositol-1,4-bisphosphate metabolism emerges from this work." [Full Text]

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Recent Bipolar Disorder & PIP2 Research

1) Yih LH, Wu YC, Hsu NC, Kuo HH
Arsenic Trioxide Induces Abnormal Mitotic Spindles Through a PIP4KIIγ/Rho Pathway.
Toxicol Sci. 2012 Jul;128(1):115-25.
Arsenite-induced spindle abnormalities result in mitotic cell apoptosis in several cancer cell lines, but how arsenite induces these effects is not known. Evidence to date has revealed that arsenite activates Rho guanosine triphosphatases (GTPases). Because Rho GTPases regulate spindle orientation, chromosome congression, and cytokinesis, we therefore examined the involvement of Rho GTPases and their modulators in arsenite-induced mitotic abnormalities. We demonstrated that arsenic trioxide (ATO) disrupted the positioning of bipolar mitotic spindles and induced centrosome and spindle abnormalities. ATO increased the level of the active guanosine triphosphate-bound form of Rho. Inhibition of Rho-associated protein kinases (ROCKs) by Y-27632 ameliorated ATO-induced spindle defects, mitotic arrest, and cell death. These results indicate that ATO may induce spindle abnormalities and mitotic cell death through a Rho/ROCK pathway. In addition, screening of a human kinase and phosphatase shRNA library to select genes that mediate ATO induction of spindle abnormalities resulted in the identification of phosphatidylinositol-5-phosphate 4-kinase type-2 gamma (PIP4KII?), a phosphatidylinositol 4,5-biphosphate (PIP2) synthesis enzyme that belongs to the phosphatidylinositol phosphate kinase (PIPK) family. Sequestration of PIP2 by ectopic overexpression of the pleckstrin homology domain of phospholipase C-?1 protected cells from ATO-induced cell death. Furthermore, depletion of PIP4KII?, but not other isoforms of the PIPK family, not only reduced Rho GTPase activation in ATO-treated cells but also alleviated ATO-induced spindle defects, mitotic arrest, and mitotic cell apoptosis. Thus, our results imply that ATO induces abnormalities in mitotic spindles through a PIP4KII?/Rho pathway, leading to apoptosis of mitotic cells. [PubMed Citation] [Order full text from Infotrieve]

2) Kimata T, Tanizawa Y, Can Y, Ikeda S, Kuhara A, Mori I
Synaptic Polarity Depends on Phosphatidylinositol Signaling Regulated by myo-Inositol Monophosphatase in Caenorhabditis elegans.
Genetics. 2012 Jun;191(2):509-21.
Although neurons are highly polarized, how neuronal polarity is generated remains poorly understood. An evolutionarily conserved inositol-producing enzyme myo-inositol monophosphatase (IMPase) is essential for polarized localization of synaptic molecules in Caenorhabditis elegans and can be inhibited by lithium, a drug for bipolar disorder. The synaptic defect of IMPase mutants causes defects in sensory behaviors including thermotaxis. Here we show that the abnormalities of IMPase mutants can be suppressed by mutations in two enzymes, phospholipase C? or synaptojanin, which presumably reduce the level of membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)). We also found that mutations in phospholipase C? conferred resistance to lithium treatment. Our results suggest that reduction of PIP(2) on plasma membrane is a major cause of abnormal synaptic polarity in IMPase mutants and provide the first in vivo evidence that lithium impairs neuronal PIP(2) synthesis through inhibition of IMPase. We propose that the PIP(2) signaling regulated by IMPase plays a novel and fundamental role in the synaptic polarity. [PubMed Citation] [Order full text from Infotrieve]

3) Wang Z, Shen J, Wang J, Lu T, Li C, Zhang X, Liu L, Ding Z
Lithium attenuates bupivacaine-induced neurotoxicity in vitro through phosphatidylinositol-3-kinase/threonine-serine protein kinase B- and extracellular signal-regulated kinase-dependent mechanisms.
Neuroscience. 2012 Mar 29;206:190-200.
Local anesthetics (LAs) are necessary for the regional anesthesia, spinal anesthesia, and pain management. However, the application of LAs may cause neurotoxicity and result in postoperative neurological complications. Lithium is a mood stabilizer for the treatment of bipolar disorder and may exert neuroprotective effects. In this study, we evaluated the effects of lithium on bupivacaine (a frequently used LAs)-induced injury in mouse neuroblastoma neuro 2a (N2a) cells. N2a cells were treated with bupivacaine in the presence or absence of lithium. After treatment, the cell injury was evaluated by examination of viability, morphology changes, and nuclear condensation. The levels of mitochondrial transmembrane potential (??m) and activation of phosphatidylinositol-3-kinase (PI3K)/ threonine-serine protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were also examined. In a separate experiment, we investigated the effect of Akt and ERK inhibition on cell injury after bupivacaine and lithium treatment. Pretreatment of N2a cells with lithium significantly attenuated bupivacaine-induced cell injury. Lithium pretreatment completely reversed the suppression of PI3K/Akt and ERK signalings and significantly prevented the decline of ??m in N2a cells after bupivacaine treatment. More importantly, pharmacological inhibition of Akt and ERK diminished the protective effect of lithium against bupivacaine-induced neuronal death. Our data suggest that lithium pretreatment provides a protective effect on bupivacaine-induced neuronal cell injury. This action of lithium is mediated through, at least in part, the activating of PI3K/Akt- and ERK-dependent mechanisms. Because lithium is a clinically proved safety drug for neurons, it is worthwhile to identify whether coadministration of LAs with lithium will decrease the risks of LAs-induced postoperative neurological complications in clinic practice. [PubMed Citation] [Order full text from Infotrieve]

4) Liu ZH, Huang T, Smith CB
Lithium reverses increased rates of cerebral protein synthesis in a mouse model of fragile X syndrome.
Neurobiol Dis. 2012 Mar;45(3):1145-52.
Individuals with fragile X syndrome (FXS), an inherited form of cognitive disability, have a wide range of symptoms including hyperactivity, autistic behavior, seizures and learning deficits. FXS is caused by silencing of FMR1 and the consequent absence of fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that associates with polyribosomes and negatively regulates translation. In a previous study of a mouse model of FXS (Fmr1 knockout (KO)) we demonstrated that in vivo rates of cerebral protein synthesis (rCPS) were elevated in selective brain regions suggesting that the absence of FMRP in FXS may result in dysregulation of cerebral protein synthesis. Lithium, a drug used clinically to treat bipolar disorder, has been used to improve mood dysregulation in individuals with FXS. We reported previously that in the Fmr1 KO mouse chronic dietary lithium treatment reversed or ameliorated both behavioral and morphological abnormalities. Herein we report that chronic dietary lithium treatment reversed the increased rCPS in Fmr1 KO mice with little effect on wild type mice. We also report our results of analyses of key signaling molecules involved in regulation of mRNA translation. Our analyses indicate that neither effects on the PI3K/Akt nor the MAPK/ERK 1/2 pathway fully account for the effects of lithium treatment on rCPS. Collectively our findings and those from other laboratories on the efficacy of lithium treatment in animal models support further studies in patients with FXS. [PubMed Citation] [Order full text from Infotrieve]

5) Wang Z, Wang J, Li J, Wang X, Yao Y, Zhang X, Li C, Cheng Y, Ding G, Liu L, Ding Z
MEK/ERKs signaling is essential for lithium-induced neurite outgrowth in N2a cells.
Int J Dev Neurosci. 2011 Jun;29(4):415-22.
Lithium, a drug used for the treatment of bipolar disorder, has been shown to affect different aspects of neuronal development such as neuritogenesis, neurogenesis and survival. The underlying mechanism responsible for lithium's influence on neuronal development, however, still remains to be elucidated. In the present study, we demonstrate that lithium increases the phosphorylation of extracellular-signal regulated kinases (ERKs) and protein kinase B (Akt) and promotes neurite outgrowth in mouse N2a neuroblastoma cells (N2a). The inactivation of mitogen-activated protein kinase kinase (MEK)/ERKs signaling with a MEK inhibitor inhibits neurite outgrowth, but it enhances Akt activation in lithium-treated N2a cells. Furthermore, the inactivation of phosphoinositide-3-kinase (PI3K)/Akt signaling with a PI3K inhibitor increases both lithium-induced ERKs activation and lithium-induced neurite outgrowth. Taken together, our study suggests that lithium-induced neurite outgrowth in N2a cells is regulated by cross-talk between the MEK/ERKs and PI3K/Akt pathways and requires the activation of the MEK/ERKs signaling. [PubMed Citation] [Order full text from Infotrieve]

6) Ludtmann MH, Boeckeler K, Williams RS
Molecular pharmacology in a simple model system: implicating MAP kinase and phosphoinositide signalling in bipolar disorder.
Semin Cell Dev Biol. 2011 Feb;22(1):105-13.
Understanding the mechanisms of drug action has been the primary focus for pharmacological researchers, traditionally using rodent models. However, non-sentient model systems are now increasingly being used as an alternative approach to better understand drug action or targets. One of these model systems, the social amoeba Dictyostelium, enables the rapid ablation or over-expression of genes, and the subsequent use of isogenic cell culture for the analysis of cell signalling pathways in pharmacological research. The model also supports an increasingly important ethical view of research, involving the reduction, replacement and refinement of animals in biomedical research. This review outlines the use of Dictyostelium in understanding the pharmacological action of two commonly used bipolar disorder treatments (valproic acid and lithium). Both of these compounds regulate mitogen activated protein (MAP) kinase and inositol phospholipid-based signalling by unknown means. Analysis of the molecular pathways targeted by these drugs in Dictyostelium and translation of discoveries to animal systems has helped to further understand the molecular mechanisms of these bipolar disorder treatments. [PubMed Citation] [Order full text from Infotrieve]

7) Popkie AP, Zeidner LC, Albrecht AM, D'Ippolito A, Eckardt S, Newsom DE, Groden J, Doble BW, Aronow B, McLaughlin KJ, White P, Phiel CJ
Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci.
J Biol Chem. 2010 Dec 31;285(53):41337-47.
Glycogen synthase kinase-3 (Gsk-3) isoforms, Gsk-3? and Gsk-3?, are constitutively active, largely inhibitory kinases involved in signal transduction. Underscoring their biological significance, altered Gsk-3 activity has been implicated in diabetes, Alzheimer disease, schizophrenia, and bipolar disorder. Here, we demonstrate that deletion of both Gsk-3? and Gsk-3? in mouse embryonic stem cells results in reduced expression of the de novo DNA methyltransferase Dnmt3a2, causing misexpression of the imprinted genes Igf2, H19, and Igf2r and hypomethylation of their corresponding imprinted control regions. Treatment of wild-type embryonic stem cells and neural stem cells with the Gsk-3 inhibitor, lithium, phenocopies the DNA hypomethylation at these imprinted loci. We show that inhibition of Gsk-3 by phosphatidylinositol 3-kinase (PI3K)-mediated activation of Akt also results in reduced DNA methylation at these imprinted loci. Finally, we find that N-Myc is a potent Gsk-3-dependent regulator of Dnmt3a2 expression. In summary, we have identified a signal transduction pathway that is capable of altering the DNA methylation of imprinted loci. [PubMed Citation] [Order full text from Infotrieve]

8) Wang LH, Xiang J, Yan M, Zhang Y, Zhao Y, Yue CF, Xu J, Zheng FM, Chen JN, Kang Z, Chen TS, Xing D, Liu Q
The mitotic kinase Aurora-A induces mammary cell migration and breast cancer metastasis by activating the Cofilin-F-actin pathway.
Cancer Res. 2010 Nov 15;70(22):9118-28.
The mitotic kinase Aurora-A (Aur-A) is required to form the bipolar spindle and ensure accurate chromosome segregation before cell division. Aur-A dysregulation represents an oncogenic event that promotes tumor formation. Here, we report that Aur-A promotes breast cancer metastasis. Aur-A overexpression enhanced mammary cell migration by dephosphorylation and activation of cofilin, which facilitates actin reorganization and polymerization. Cofilin knockdown impaired Aur-A-driven cell migration and protrusion of the cell membrane. Conversely, overexpression of activated cofilin abrogated the effects of Aur-A knockdown on cell migration. Moreover, Aur-A overexpession increased the expression of the cofilin phosphatase Slingshot-1 (SSH1), contributing to cofilin activation and cell migration. We found that phosphatidylinositol 3-kinase (PI3K) inhibition blocked Aur-A-induced cofilin dephosphorylation, actin reorganization, and cell migration, suggesting crosstalk with PI3K signaling and a potential benefit of PI3K inhibition in tumors with deregulated Aur-A. Additionally, we found an association between Aur-A overexpression and cofilin activity in breast cancer tissues. Our findings indicate that activation of the cofilin-F-actin pathway contributes to tumor cell migration and metastasis enhanced by Aur-A, revealing a novel function for mitotic Aur-A kinase in tumor progression. [PubMed Citation] [Order full text from Infotrieve]

9) Pilot-Storck F, Chopin E, Rual JF, Baudot A, Dobrokhotov P, Robinson-Rechavi M, Brun C, Cusick ME, Hill DE, Schaeffer L, Vidal M, Goillot E
Interactome mapping of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway identifies deformed epidermal autoregulatory factor-1 as a new glycogen synthase kinase-3 interactor.
Mol Cell Proteomics. 2010 Jul;9(7):1578-93.
The phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR) pathway plays pivotal roles in cell survival, growth, and proliferation downstream of growth factors. Its perturbations are associated with cancer progression, type 2 diabetes, and neurological disorders. To better understand the mechanisms of action and regulation of this pathway, we initiated a large scale yeast two-hybrid screen for 33 components of the PI3K-mTOR pathway. Identification of 67 new interactions was followed by validation by co-affinity purification and exhaustive literature curation of existing information. We provide a nearly complete, functionally annotated interactome of 802 interactions for the PI3K-mTOR pathway. Our screen revealed a predominant place for glycogen synthase kinase-3 (GSK3) A and B and the AMP-activated protein kinase. In particular, we identified the deformed epidermal autoregulatory factor-1 (DEAF1) transcription factor as an interactor and in vitro substrate of GSK3A and GSK3B. Moreover, GSK3 inhibitors increased DEAF1 transcriptional activity on the 5-HT1A serotonin receptor promoter. We propose that DEAF1 may represent a therapeutic target of lithium and other GSK3 inhibitors used in bipolar disease and depression. [PubMed Citation] [Order full text from Infotrieve]

10) Fabian L, Wei HC, Rollins J, Noguchi T, Blankenship JT, Bellamkonda K, Polevoy G, Gervais L, Guichet A, Fuller MT, Brill JA
Phosphatidylinositol 4,5-bisphosphate directs spermatid cell polarity and exocyst localization in Drosophila.
Mol Biol Cell. 2010 May 1;21(9):1546-55.
During spermiogenesis, Drosophila melanogaster spermatids coordinate their elongation in interconnected cysts that become highly polarized, with nuclei localizing to one end and sperm tail growth occurring at the other. Remarkably little is known about the signals that drive spermatid polarity and elongation. Here we identify phosphoinositides as critical regulators of these processes. Reduction of plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)) by low-level expression of the PIP(2) phosphatase SigD or mutation of the PIP(2) biosynthetic enzyme Skittles (Sktl) results in dramatic defects in spermatid cysts, which become bipolar and fail to fully elongate. Defects in polarity are evident from the earliest stages of elongation, indicating that phosphoinositides are required for establishment of polarity. Sktl and PIP(2) localize to the growing end of the cysts together with the exocyst complex. Strikingly, the exocyst becomes completely delocalized when PIP(2) levels are reduced, and overexpression of Sktl restores exocyst localization and spermatid cyst polarity. Moreover, the exocyst is required for polarity, as partial loss of function of the exocyst subunit Sec8 results in bipolar cysts. Our data are consistent with a mechanism in which localized synthesis of PIP(2) recruits the exocyst to promote targeted membrane delivery and polarization of the elongating cysts. [PubMed Citation] [Order full text from Infotrieve]

11) Javadi-Paydar M, Vojdanpak S, Pour-Ali M, Halajian H, Ghazi P, Shahsavari F, Emami-Razavi SH, Dehpour AR
Effect of lithium on secretory factors and growth stimulation by bombesin in rat pancreas and salivary glands.
Chin J Physiol. 2010 Feb 28;53(1):26-35.
Lithium, a drug of choice in bipolar affective disorders, also affects the metabolism and cell proliferation in a diverse array of organisms. In this study, we investigated the effect of lithium on bombesin-mediated function in excretion and growth of the pancreas and the salivary glands. The weight, protein content, amylase concentration and salivary flow rate of the pancreas, parotid and the submandibular glands were determined in male Wistar rats after consumption of either water or lithium chloride (600 mg/l) for 14 days and each group received s.c. injection of either saline or bombesin (10 microg/kg) during the last 4 days of experiment. Our results revealed that administration of bombesin in lithium-treated group not only suppressed pancreas and parotid weight augmentation due to bombesin, but also significantly decreased pancreas growth. Chronic lithium consumption significantly inhibited the protein content augmentation due to bombesin in the salivary glands. Getting bombesin, as well as saline in lithium-treated group, resulted in notable decrease in salivary protein content. Protein content of pancreatic gland increased considerably in the bombesin-injected groups either treated with saline or lithium. In conclusion, the stimulatory effect of bombesin on the growth and protein content of the pancreas and the salivary gland was inhibited by lithium. Lithium seems to be a potent inhibitor of growth factors induced by bombesin probably through inhibiting phosphatidylinositol 4,5,bisphosphate hydrolysis. [PubMed Citation] [Order full text from Infotrieve]

12) Kanemaru K, Nakahara M, Nakamura Y, Hashiguchi Y, Kouchi Z, Yamaguchi H, Oshima N, Kiyonari H, Fukami K
Phospholipase C-eta2 is highly expressed in the habenula and retina.
Gene Expr Patterns. 2010 Feb-Mar;10(2-3):119-26.
Phospholipase C (PLC), a key enzyme involved in phosphoinositide turnover, hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate two second messengers, inositol 1,4,5-triphosphate and diacylglycerol. PLCeta2 (PLCeta2), a neuron-specific isozyme of PLC, is abundantly expressed in the postnatal brain, suggesting the importance of PLCeta2 in the formation and maintenance of the neuronal network in the postnatal brain. However, the detailed expression patterns of PLCeta2 in the brain and other neuronal tissues remain to be clarified. Here, we generated PLCeta2 knockout/LacZ knockin (plch2(lacZ)(/)(lacZ)) mice-the first mice to lack full-length PLCeta2. Although the plch2(lacZ)(/)(lacZ) mice exhibited no obvious abnormalities, the LacZ reporter revealed unexpected and abundant expressions of PLCeta2 in the habenula and retina. We confirmed these PLCeta2 expression patterns by in situ hybridization and immunohistochemical analyses. In the retina, strong PLCeta2 expression was detected in the photoreceptor (rod/cone), outer nuclear layer, outer plexiform layer, and inner nuclear layer, suggesting that PLCeta2 is expressed in rods and cones, and also in horizontal, bipolar, and amacrine cells, but not in ganglion cells. Interestingly PLCeta2 exhibited a dynamic expression pattern during postnatal retinal development, strongly suggesting that this isozyme might be involved in the development and maturation of the retina. Since both the habenula and retina are thought to play important roles in the regulation of circadian rhythms, our results suggest that PLCeta2 may be involved in the function of habenula and retina. [PubMed Citation] [Order full text from Infotrieve]

13) Pawolleck N, Williams RS
Quantifying in vivo phosphoinositide turnover in chemotactically competent Dictyostelium cells.
Methods Mol Biol. 2009;571:283-90.
Phosphoinositide (PI) signalling is one of multiple signalling cascades involved in chemotaxis in Dictyostelium discoideum. PI signalling comprises a complex interaction of multiple enzymes, each with multiple phospholipid substrates and thus products, often relying upon several enzymes in series to produce a signal. PI turnover, controlled by both kinases and phosphatases, is also rapidly triggered and spatially constricted. This complexity makes understanding acute regulation of these signalling components problematic. However, the ubiquitous and extensive roles of phospholipids, including phosphatidylinositol-4,5-diphosphate (PI(4,5)P(2)), in cell signalling and developmental processes make understanding the production of these compounds of great importance. We have shown the acute reduction of PI phosphorylation in response to a widely used bipolar disorder and epilepsy treatment, valproic acid, as a potential therapeutic role for the drug using chemotactically competent Dictyostelium. Here we describe a means for measuring acute in vivo phospholipid labelling in Dictyostelium. [PubMed Citation] [Order full text from Infotrieve]

14) Teo R, King J, Dalton E, Ryves J, Williams RS, Harwood AJ
PtdIns(3,4,5)P(3) and inositol depletion as a cellular target of mood stabilizers.
Biochem Soc Trans. 2009 Oct;37(Pt 5):1110-4.
Lithium (Li(+)) is the mood stabilizer most frequently used in the treatment of bipolar mood disorder; however, its therapeutic mechanism is unknown. In the 1980s, Berridge and colleagues proposed that Li(+) treatment acts via inhibition of IMPase (inositol monophosphatase) to deplete the cellular concentration of myo-inositol. Inositol depletion is also seen with the alternative mood stabilizers VPA (valproic acid) and CBZ (carbamazepine), suggesting a common therapeutic action. All three drugs cause changes in neuronal cell morphology and cell chemotaxis; however, it is unclear how reduced cellular inositol modulates these changes in cell behaviour. It is often assumed that reduced inositol suppresses Ins(1,4,5)P(3), a major intracellular signal molecule, but there are other important phosphoinostide-based signal molecules in the cell. In the present paper, we discuss evidence that Li(+) has a substantial effect on PtdIns(3,4,5)P(3), an important signal molecule within the nervous system. As seen for Ins(1,4,5)P(3) signalling, suppression of PtdIns(3,4,5)P(3) signalling also occurs via an inositol-depletion mechanism. This has implications for the cellular mechanisms controlling phosphoinositide signalling, and offers insight into the genetics underlying risk of bipolar mood disorder. [PubMed Citation] [Order full text from Infotrieve]

15) Deranieh RM, Greenberg ML
Cellular consequences of inositol depletion.
Biochem Soc Trans. 2009 Oct;37(Pt 5):1099-103.
The inositol-depletion hypothesis was suggested to explain the therapeutic mechanism of mood-stabilizing drugs. Focus was previously on the phosphatidylinositol signalling pathway and on the regulatory roles of Ins(3,4,5)P(3) and DAG (diacylglycerol). Recent findings indicate that inositol and inositol-containing molecules, including phosphoinositides and inositol phosphates, have signalling and regulatory roles in many cellular processes. This suggests that depleting inositol may lead to perturbation of a wide range of cellular functions, at least some of which may be associated with bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

16) Mizutani R, Yamauchi J, Kusakawa S, Nakamura K, Sanbe A, Torii T, Miyamoto Y, Tanoue A
Sorting nexin 3, a protein upregulated by lithium, contains a novel phosphatidylinositol-binding sequence and mediates neurite outgrowth in N1E-115 cells.
Cell Signal. 2009 Nov;21(11):1586-94.
Lithium, a drug in the treatment of bipolar disorder, modulates many aspects of neuronal developmental processes such as neurogenesis, survival, and neuritogenesis. However, the underlying mechanism still remains to be understood. Here, we show that lithium upregulates the expression of sorting nexin 3 (SNX3), one of the Phox (PX) domain-containing proteins involved in endosomal sorting, and regulates neurite outgrowth in mouse N1E-115 neuroblastoma cells. The inhibition of SNX3 function by its knockdown decreases lithium-induced outgrowth of neurites. Transfection of the full-length SNX3 construct into cells facilitates the outgrowth. We also find that the C-terminus, as well as the PX domain, of SNX3 has a functional binding sequence with phosphatidylinositol monophosphates. Transfection of the C-terminal deletion mutant or only the C-terminus does not have an effect on the outgrowth. These results suggest that SNX3, a protein upregulated by lithium, is an as yet unknown regulator of neurite formation and that it contains another functional phosphatidylinositol phosphate-binding region at the C-terminus. [PubMed Citation] [Order full text from Infotrieve]

17) Houlihan LM, Christoforou A, Arbuckle MI, Torrance HS, Anderson SM, Muir WJ, Porteous DJ, Blackwood DH, Evans KL
A case-control association study and family-based expression analysis of the bipolar disorder candidate gene PI4K2B.
J Psychiatr Res. 2009 Dec;43(16):1272-7.
Bipolar disorder, schizophrenia and recurrent major depression are complex psychiatric illnesses with a substantial, yet unknown genetic component. Linkage of bipolar disorder and recurrent major depression with markers on chromosome 4p15-p16 has been identified in a large Scottish family and three smaller families. Analysis of haplotypes in the four chromosome 4p-linked families, identified two regions, each shared by three of the four families, which are also supported by a case-control association study. The candidate gene phosphatidylinositol 4-kinase type-II beta (PI4K2B) lies within one of these regions. PI4K2B is a strong functional candidate as it is a member of the phosphatidylinositol pathway, which is targeted by lithium for therapeutic effect in bipolar disorder. Two approaches were undertaken to test the PI4K2B candidate gene as a susceptibility factor for psychiatric illness. First, a case-control association study, using tagging SNPs from the PI4K2B genomic region, in bipolar disorder (n=368), schizophrenia (n=386) and controls (n=458) showed association with a two-marker haplotype in schizophrenia but not bipolar disorder (rs10939038 and rs17408391, global P=0.005, permuted global P=0.039). Second, expression studies at the allele-specific mRNA and protein level using lymphoblastoid cell lines from members of the large Scottish family, which showed linkage to 4p15-p16 in bipolar disorder and recurrent major depression, showed no difference in expression differences between affected and non-affected family members. There is no evidence to suggest that PI4K2B is contributing to bipolar disorder in this family but a role for this gene in schizophrenia has not been excluded. [PubMed Citation] [Order full text from Infotrieve]

18) Thiselton DL, Maher BS, Webb BT, Bigdeli TB, O'Neill FA, Walsh D, Kendler KS, Riley BP
Association analysis of the PIP4K2A gene on chromosome 10p12 and schizophrenia in the Irish study of high density schizophrenia families (ISHDSF) and the Irish case-control study of schizophrenia (ICCSS).
Am J Med Genet B Neuropsychiatr Genet. 2010 Jan 5;153B(1):323-31.
Molecular studies support pharmacological evidence that phosphoinositide signaling is perturbed in schizophrenia and bipolar disorder. The phosphatidylinositol-4-phosphate-5-kinase type-II alpha (PIP4K2A) gene is located on chromosome 10p12. This region has been implicated in both diseases by linkage, and PIP4K2A directly by association. Given linkage evidence in the Irish Study of High Density Schizophrenia Families (ISHDSF) to a region including 10p12, we performed an association study between genetic variants at PIP4K2A and disease. No association was detected through single-marker or haplotype analysis of the whole sample. However, stratification into families positive and negative for the ISHDSF schizophrenia high-risk haplotype (HRH) in the DTNBP1 gene and re-analysis for linkage showed reduced amplitude of the 10p12 linkage peak in the DTNBP1 HRH positive families. Association analysis of the stratified sample showed a trend toward association of PIP4K2A SNPs rs1417374 and rs1409395 with schizophrenia in the DTNBP1 HRH positive families. Despite this apparent paradox, our data may therefore suggest involvement of PIP4K2A in schizophrenia in those families for whom genetic variation in DTNBP1 appears also to be a risk factor. This trend appears to arise from under-transmission of common alleles to female cases. Follow-up association analysis in a large Irish schizophrenia case-control sample (ICCSS) showed significant association with disease of a haplotype comprising these same SNPs rs1417374-rs1409395, again more so in affected females, and in cases with negative family history of the disease. This study supports a minor role for PIP4K2A in schizophrenia etiology in the Irish population. [PubMed Citation] [Order full text from Infotrieve]

19) King JS, Teo R, Ryves J, Reddy JV, Peters O, Orabi B, Hoeller O, Williams RS, Harwood AJ
The mood stabiliser lithium suppresses PIP3 signalling in Dictyostelium and human cells.
Dis Model Mech. 2009 May-Jun;2(5-6):306-12.
Bipolar mood disorder (manic depression) is a major psychiatric disorder whose molecular origins are unknown. Mood stabilisers offer patients both acute and prophylactic treatment, and experimentally, they provide a means to probe the underlying biology of the disorder. Lithium and other mood stabilisers deplete intracellular inositol and it has been proposed that bipolar mood disorder arises from aberrant inositol (1,4,5)-trisphosphate [IP(3), also known as Ins(1,4,5)P(3)] signalling. However, there is no definitive evidence to support this or any other proposed target; a problem exacerbated by a lack of good cellular models. Phosphatidylinositol (3,4,5)-trisphosphate [PIP(3), also known as PtdIns(3,4,5)P(3)] is a prominent intracellular signal molecule within the central nervous system (CNS) that regulates neuronal survival, connectivity and synaptic function. By using the genetically tractable organism Dictyostelium, we show that lithium suppresses PIP(3)-mediated signalling. These effects extend to the human neutrophil cell line HL60. Mechanistically, we show that lithium attenuates phosphoinositide synthesis and that its effects can be reversed by overexpression of inositol monophosphatase (IMPase), consistent with the inositol-depletion hypothesis. These results demonstrate a lithium target that is compatible with our current knowledge of the genetic predisposition for bipolar disorder. They also suggest that lithium therapy might be beneficial for other diseases caused by elevated PIP(3) signalling. [PubMed Citation] [Order full text from Infotrieve]

20) Di Daniel E, Glover CP, Grot E, Chan MK, Sanderson TH, White JH, Ellis CL, Gallagher KT, Uney J, Thomas J, Maycox PR, Mudge AW
Prolyl oligopeptidase binds to GAP-43 and functions without its peptidase activity.
Mol Cell Neurosci. 2009 Jul;41(3):373-82.
Inhibitors of the enzyme prolyl oligopeptidase (PO) improve performance in rodent learning and memory tasks. PO inhibitors are also implicated in the action of drugs used to treat bipolar disorder: they reverse the effects of three mood stabilizers on the dynamic behaviour of neuronal growth cones. PO cleaves prolyl bonds in short peptides, suggesting that neuropeptides might be its brain substrates. PO is located in the cytosol, however, where it would not contact neuropeptides. Here, we show that mice with a targeted PO null-mutation have altered growth cone dynamics. The wild-type phenotype is restored by PO cDNAs encoding either native or a catalytically-dead enzyme. In addition, we show that PO binds to the growth-associated protein GAP-43, which is a key regulator of synaptic plasticity. Taken together, our results show that peptidase activity is not required for PO function in neurons and suggest that PO instead acts by binding to cytosolic proteins that control growth cone and synaptic function. [PubMed Citation] [Order full text from Infotrieve]