PIP2 and Bipolar Disorder -- Neurotransmitter.net

(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. 3.1.3.25) 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) Xia Y, Wang CZ, Liu J, Anastasio NC, Johnson KM
Lithium Protection of Phencyclidine-induced Neurotoxicity in Developing Brain: The Role PI-3K/Akt and MEK/ERK Signaling Pathways.
J Pharmacol Exp Ther. 2008 Jun 10;
Phencyclidine (PCP) and other N-methyl-D-aspartate (NMDA) receptor antagonists have been shown to be neurotoxic to developing brains and to result in schizophrenia-like behaviors later in development. Prevention of both effects by antischizophrenic drugs suggests the validity of PCP neurodevelopmental toxicity as a heuristic model of schizophrenia. Lithium is used for the treatment of bipolar and schizoaffective disorders and has recently been shown to have neuroprotective properties. The present study used organotypic corticostriatal slices taken from postnatal day 2 rat pups to investigate the protective effect of lithium and the role of the phosphatidylinositol-3 kinase (PI-3K)/Akt and mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) pathways in PCP-induced cell death. Lithium pretreatment dose-dependently reduced PCP-induced caspase-3 activation and DNA fragmentation in layer II-IV of the cortex. PCP elicited time-dependent inhibition of the MEK/ERK and PI-3K/Akt pathways, as indicated by dephosphorylation of ERK1/2 and Akt. The pro-apoptotic factor glycogen synthase kinase-3beta (GSK-3beta) was also dephosphorylated at serine 9 and thus activated. Lithium prevented PCP-induced inhibition of the two pathways and activation of GSK-3beta. Furthermore, blocking either PI-3K/Akt or MEK/ERK pathway abolished the protective effect of lithium, while inhibiting GSK-3beta activity mimicked the protective effect of lithium. However, no crosstalk between the two pathways was found. Finally, specific GSK-3beta inhibition did not prevent PCP-induced dephosphorylation of Akt and ERK. These data strongly suggest that the protective effect of lithium against PCP-induced neuroapoptosis is mediated through independent stimulation of the PI-3K/Akt and ERK pathways and suppression of GSK-3beta activity. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

2) McGrath BM, McKay R, Dave S, Seres P, Weljie AM, Slupsky CM, Hanstock CC, Greenshaw AJ, Silverstone PH
Acute dextro-amphetamine administration does not alter brain myo-inositol levels in humans and animals: MRS investigations at 3 and 18.8T.
Neurosci Res. 2008 Aug;61(4):351-9.
The pathophysiological underpinnings of bipolar disorder are not fully understood. However, they may be due in part to changes in the phosphatidylinositol second messenger system (PI-cycle) generally, or changes in myo-inositol concentrations more specifically. Dextro-amphetamine has been used as a model for mania in several human studies as it causes similar subjective and physiological symptoms. We wanted to determine if dextro-amphetamine altered myo-inositol concentrations in vivo as it would clearly define a mechanism linking putative changes in the PI-cycle to the subjective psychological changes seen with dextro-amphetamine administration. Fifteen healthy human volunteers received a baseline scan, followed by second scan 75min after receiving a 25mg oral dose of dextro-amphetamine. Stimulated echo proton magnetic resonance spectroscopy (MRS) scans were preformed at 3.0Tesla (T) in the dorsal medial prefrontal cortex (DMPFC). Metabolite data were adjusted for tissue composition and analyzed using LCModel. Twelve adult male rats were treated acutely with a 5-mg/kg intraperitoneal dose of dextro-amphetamine. After 1h rats were decapitated and the brains were rapidly removed and frozen until dissection. Rat brains were dissected into frontal, temporal, and occipital cortical areas, as well as hippocampus. Tissue was analyzed using a Varian 18.8T spectrometer. Metabolites were identified and quantified using Chenomx Profiler software. The main finding in the present study was that myo-inositol concentrations in the DMPFC of human volunteers and in the four rat brain regions were not altered by acute dextro-amphetamine. While it remains possible that the PI-cycle may be involved in the pathophysiology of bipolar disorder, it is not likely that the subjective and physiological of dextro-amphetamine are mediated, directly or indirectly, via alternations in myo-inositol concentrations. [PubMed Citation] [Order full text from Infotrieve]

3) Choudhary SK, Archin NM, Margolis DM
Hexamethylbisacetamide and disruption of human immunodeficiency virus type 1 latency in CD4(+) T cells.
J Infect Dis. 2008 Apr 15;197(8):1162-70.
BACKGROUND: Novel therapeutic approaches are needed to attack persistent proviral human immunodeficiency type 1 (HIV-1) infection. Hexamethylbisacetamide (HMBA), a hybrid bipolar compound, induces expression of the HIV-1 promoter in the long terminal repeat (LTR) region in a Tat-independent manner but mimics the effect of Tat, overcoming barriers to LTR expression and increasing the processivity of LTR transcription complexes. METHODS: We studied alterations in cellular factors and their LTR occupancy induced by HMBA in models of latent HIV-1 infection. We measured the induction of viral outgrowth by HMBA in resting CD4(+) T cells from aviremic HIV-1-infected donors. RESULTS: HMBA induced outgrowth of HIV-1 from resting CD4(+) T cells recovered from aviremic patients treated with antiretroviral therapy (ART). HMBA triggered cyclin-dependent kinase 9 (CDK9) recruitment to the LTR, a key factor in the induction of efficient HIV-1 expression, via an unexpected interaction with the transcription factor Sp1. The availability of Sp1 and Sp1 DNA binding sites were necessary for HMBA-induced CDK9 recruitment and LTR expression. HMBA signaling via both protein kinase C mu and phosphatidylinositol 3-kinase appeared to contribute to LTR induction. CONCLUSIONS: The novel mechanism through which HMBA disrupts latent HIV-1 infection involves 2 cellular kinases that may be therapeutically exploited to induce expression of persistent proviral HIV-1. [PubMed Citation] [Order full text from Infotrieve]

4) Tokuoka SM, Saiardi A, Nurrish SJ
The Mood Stabilizer Valproate Inhibits both Inositol- and Diacylglycerol-signaling Pathways in Caenorhabditis elegans.
Mol Biol Cell. 2008 May;19(5):2241-50.
The antiepileptic valproate (VPA) is widely used in the treatment of bipolar disorder, although the mechanism of its action in the disorder is unclear. We show here that VPA inhibits both inositol phosphate and diacylglycerol (DAG) signaling in Caenorhabditis elegans. VPA disrupts two behaviors regulated by the inositol-1,4,5-trisphosphate (IP(3)): defecation and ovulation. VPA also inhibits two activities regulated by DAG signaling: acetylcholine release and egg laying. The effects of VPA on DAG signaling are relieved by phorbol ester, a DAG analogue, suggesting that VPA acts to inhibit DAG production. VPA reduces levels of DAG and inositol-1-phosphate, but phosphatidylinositol-4,5-bisphosphate (PIP(2)) is slightly increased, suggesting that phospholipase C-mediated hydrolysis of PIP(2) to form DAG and IP(3) is defective in the presence of VPA. [PubMed Citation] [Order full text from Infotrieve]

5) McGrath BM, Greenshaw AJ, McKay R, Slupsky CM, Silverstone PH
Unlike lithium, anticonvulsants and antidepressants do not alter rat brain myo-inositol.
Neuroreport. 2007 Oct 8;18(15):1595-8.
Lithium is the first-line in bipolar disorder treatment. Lithium's clinical efficacy might be due to its inhibition of myo-inositol turnover in the phosphatidylinositol second messenger system. This study aimed to determine whether this action can extend to antidepressants and anticonvulsants also used to treat bipolar symptoms. Male rats were treated for 2 weeks with an intraperitoneal injection of phenelzine, fluoxetine, desipramine, carbamazepine, lamotrigine, sodium valproate or vehicle. Brains were dissected and myo-inositol concentrations were analyzed using high-field nuclear magnetic resonance spectroscopy at 18.8 T and quantified using Chenomx Profiler software. Brain regions assessed included the prefrontal, temporal and occipital cortical areas as well as the hippocampus. The main finding is that contrary to lithium, the anticonvulsants and antidepressants do not alter brain myo-inositol concentration. This suggests that these agents might work via a mechanism that is not centered on changes in myo-inositol concentration. [PubMed Citation] [Order full text from Infotrieve]

6) Thiselton DL, Vladimirov VI, Kuo PH, McClay J, Wormley B, Fanous A, O'Neill FA, Walsh D, Van den Oord EJ, Kendler KS, Riley BP
AKT1 is associated with schizophrenia across multiple symptom dimensions in the Irish study of high density schizophrenia families.
Biol Psychiatry. 2008 Mar 1;63(5):449-57.
BACKGROUND: The phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also been implicated in schizophrenia by association studies and decreased protein expression in the brains of schizophrenic patients. METHODS: The association of DTNBP1 in the Irish Study of High Density Schizophrenia Families (ISHDSF) prompted our investigation of AKT1 for association with disease in this sample. Eight single nucleotide polymorphisms spanning AKT1 were analyzed for association with schizophrenia across four definitions of affection and according to Operational Criteria Checklist of Psychotic Illness (OPCRIT) symptom scales. We examined expression of AKT1 messenger RNA from postmortem brain tissue of schizophrenic, bipolar, and control individuals. RESULTS: No single marker showed significant association, but the risk haplotype previously found over-transmitted to Caucasian schizophrenic patients was significantly under-transmitted in the ISHDSF (.01 < p < .05), across all OPCRIT symptom dimensions. Exploratory haplotype analysis confirmed association with schizophrenia toward the 5' end of AKT1 (.008 < p < .049, uncorrected). We found significantly decreased RNA levels in prefrontal cortex of schizophrenic individuals, consistent with reduced AKT1 protein levels reported in schizophrenic brain. CONCLUSIONS: The replication of association of AKT1 gene variants in a further Caucasian family sample adds support for involvement of AKT signaling in schizophrenia, perhaps encompassing a broader clinical phenotype that includes mood dysregulation. We show that AKT signaling might be compromised in schizophrenic and bipolar patients via reduced RNA expression of specific AKT isoforms. [PubMed Citation] [Order full text from Infotrieve]

7) Mazza M, Di Nicola M, Della Marca G, Janiri L, Bria P, Mazza S
Bipolar disorder and epilepsy: a bidirectional relation? Neurobiological underpinnings, current hypotheses, and future research directions.
Neuroscientist. 2007 Aug;13(4):392-404.
A number of studies have demonstrated that affective disorders in epilepsy represent a common psychiatric comorbidity; however, most of the classic neuropsychiatric literature focuses on depression, which is actually prominent, but little is known about bipolar depression, and very little about mania, in epilepsy. Biochemical, structural, and functional abnormalities in primary bipolar disorder could also occur secondary to seizure disorders. The kindling paradigm, invoked as a model for understanding seizure disorders, has also been applied to the episodic nature of bipolar disorder. In bipolar patients, changes in second-messenger systems, such as G-proteins, phosphatidylinositol, protein kinase C, myristoylated alanine-rich C kinase substrate, or calcium activity have been described, along with changes in c-fos expression. Common mechanisms at the level of ion channels might include the antikindling and the calcium-antagonistic and potassium outward current-modulating properties of antiepileptic drugs. All these lines of research appear to be converging on a richer understanding of neurobiological underpinnings between bipolar disorder and epilepsy. Mania, which is the other side of the coin in affective disorders, may represent a privileged window into the neurobiology of mood regulation and the neurobiology of epilepsy itself. Future research on intracellular mechanisms might become decisive for a better understanding of the similarities between these two disorders. [PubMed Citation] [Order full text from Infotrieve]

8) McQuillin A, Rizig M, Gurling HM
A microarray gene expression study of the molecular pharmacology of lithium carbonate on mouse brain mRNA to understand the neurobiology of mood stabilization and treatment of bipolar affective disorder.
Pharmacogenet Genomics. 2007 Aug;17(8):605-17.
OBJECTIVES: Lithium is the most widely prescribed and effective mood-stabilizing drug used for the treatment of bipolar affective disorder. To understand how lithium produces changes in the brain, we studied brain mRNA from 10 mice after treatment with lithium and compared them with 10 untreated controls. METHODS: We used the MAS 5.0, Smudge miner, GC-RMA and FDR-AME packages of software (Bioconductor, Seattle, Washington, USA) to determine gene expression changes using Affymetrix MOE430E 2.0 microarrays after 2 weeks of lithium treatment. RESULTS: We used both a false discovery rate (FDR-AME) assessment of significance and the Bonferroni method to correct for the possibility of false-positive changes in gene expression among the 39,000 genes present in each array. Our primary method of analysis was to use t-tests on normalized gene expression intensities. By using a Bonferroni correction of P<1.28x10(-6), we found that 121 genes showed significant changes in expression. The three genes with the most changed mRNA expression were alanine-glyoxylate aminotransferase 2-like 1 (Agxt2l1), c-mer proto-oncogene tyrosine kinase (Mertk) and sulfotransferase family 1A phenol-preferring member 1 (Sult1a1). Also among the group of 121 genes with significant changes in gene expression that survived Bonferroni correction () were the genes encoding the Per2 period gene (Per2 P=1.33x10(-8), 2.47-fold change), the metabotropic glutamate receptor (Grm3, P=9.48x10(-7), 0.7-fold change) and secretogranin II (Scg2, P=9.48x10(-7), 1.28-fold change) as well as several myelin-related genes and protein phosphatases. By taking a significance value of P<0.05 without Bonferroni or FDR-AME correction, we identified a total of 4474 genes showing changed mRNA expression in response to lithium. FDR-AME analysis showed that 1027 out of these 4474 genes were significantly changed in expression. Among the mRNAs that were significantly changed with t-tests and FDR-AME were several that had already been implicated in response to lithium such as increased brain-derived neurotrophic factor mRNA ( t-test P=0.0008-0.0005, FDR-AME P=0.0396-0.0393, 1.44-fold change) beta-phosphatidylinositol transfer protein (Pitpnb, t-test P<0.0000, FDR-AME P=0.003, 1.26-fold change) and inositol (myo)-1(or 4)-monophosphatase 1(Impa1, t test P<0.0000, FDR-AME P=0.004, 1.22-fold change). Of interest in relation to the side effect of hypothyroidism, which is caused by long-term lithium treatment was the fact that we observed changes in mRNA expression in five genes related to thyroxine metabolism. These included deiodinase (Dio2 t-test P=0.000003-0.004, FDR-AME P=0.0048-0.061, 1.53-fold change) and thyroid hormone receptor interactor 12 (Trip12, t-test P=0.003, FDR-AME P=0.075, 1.19-fold change). Of relevance to multiple sclerosis was the observed upregulation of the long isoform of myelin basic protein (t-test P=0.00013, FDR-AME P=0.0169). Changes in mRNA expression were found in 45 genes related to phosphatidylinositol metabolism using uncorrected t-tests but only 13 genes after FDR-AME. Thus, our work confirms the considerable previous research implicating this system. Gene ontology analysis showed that lithium significantly affected a cluster of processes associated with nucleotide and nucleoside metabolism. The analysis showed that there were 170 genes expressing RNA described as having ATP-binding or ATPase activity that had changed mRNA expression. The changes found have been discussed in relation to previous experimental work on the pharmacology of lithium. [PubMed Citation] [Order full text from Infotrieve]

9) Hammond GR, Schiavo G
Polyphosphoinositol lipids: under-PPInning synaptic function in health and disease.
Dev Neurobiol. 2007 Aug;67(9):1232-47.
Phosphoinositides (PPIn) form a unique family of lipids derived by phosphorylation of the parent compound, phosphatidylinositol. Despite being minor constituents of synaptic membranes, these lipids have exceptionally high rates of metabolic turnover and are involved with myriad aspects of pre- and post-synaptic function, from the control of the synaptic vesicle cycle to postsynaptic excitability. In this review, we outline the main synaptic processes known to be regulated by these molecules, focusing mainly but not exclusively on the major species phosphatidylinositol 4-phosphate and phosphatidylinositol (4,5)-bisphosphate. Furthermore, we discuss the enzymes responsible for their synthesis and degradation, with a view to exploring how the activity-dependent control of their enzymatic action can lead to the precise regulation of PPIn levels at the nerve terminal. Also, the modulation of synaptic PPIn turnover by drugs used for the treatment of bipolar disorder is discussed. We propose that the modulation of PPIn levels may act as a central mechanism to coordinate the cascade of synaptic events leading to neurotransmission. [PubMed Citation] [Order full text from Infotrieve]

10) Rosenberg G
The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees?
Cell Mol Life Sci. 2007 Aug;64(16):2090-103.
After more than 40 years of clinical use, the mechanisms of action of valproate in epilepsy, bipolar disorder and migraine are still not fully understood. However, recent findings reviewed here shed new light on the cellular effects of valproate. Beyond the enhancement of gamma-aminobutyric acid-mediated neurotransmission, valproate has been found to affect signalling systems like the Wnt/beta-catenin and ERK pathways and to interfere with inositol and arachidonate metabolism. Nevertheless, the clinical relevance of these effects is not always clear. Valproate treatment also produces marked alterations in the expression of multiple genes, many of which are involved in transcription regulation, cell survival, ion homeostasis, cytoskeletal modifications and signal transduction. These alterations may well be relevant to the therapeutic effects of valproate, and result from its enhancement of activator protein-1 DNA binding and direct inhibition of histone deacetylases, and possibly additional, yet unknown, mechanism(s). Most likely, both immediate biochemical and longer-term genomic influences underlie the effects of valproate in all three indications. [PubMed Citation] [Order full text from Infotrieve]

11) Xu X, M�ller-Taubenberger A, Adley KE, Pawolleck N, Lee VW, Wiedemann C, Sihra TS, Maniak M, Jin T, Williams RS
Attenuation of phospholipid signaling provides a novel mechanism for the action of valproic acid.
Eukaryot Cell. 2007 Jun;6(6):899-906.
Valproic acid (VPA) is used to treat epilepsy and bipolar disorder and to prevent migraine. It is also undergoing trials for cancer therapy. However, the biochemical and molecular biological actions of VPA are poorly understood. Using the social amoeba Dictyostelium discoideum, we show that an acute effect of VPA is the inhibition of chemotactic cell movement, a process partially dependent upon phospholipid signaling. Analysis of this process shows that VPA attenuates the signal-induced translocation of PH(Crac)-green fluorescent protein from cytosol to membrane, suggesting the inhibition of phosphatidylinositol-(3,4,5)-trisphosphate (PIP(3)) production. Direct labeling of lipids in vivo also shows a reduction in PIP and PIP(2) phosphorylation following VPA treatment. We further show that VPA acutely reduces endocytosis and exocytosis-processes previously shown to be dependent upon PIP(3) production. These results suggest that in Dictyostelium, VPA rapidly attenuates phospholipid signaling to reduce endocytic trafficking. To examine this effect in a mammalian model, we also tested depolarization-dependent neurotransmitter release in rat nerve terminals, and we show that this process is also suppressed upon application of VPA and an inhibitor of phosphatidylinositol 3-kinase. Although a more comprehensive analysis of the effect of VPA on lipid signaling will be necessary in mammalian systems, these results suggest that VPA may function to reduce phospholipid signaling processes and thus may provide a novel therapeutic effect for this drug. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

12) Janelle-Montcalm A, Boileau C, Poirier F, Pelletier JP, Gu�vremont M, Duval N, Martel-Pelletier J, Reboul P
Extracellular localization of galectin-3 has a deleterious role in joint tissues.
Arthritis Res Ther. 2007;9(1):R20.
In this study we examine the extracellular role of galectin-3 (gal-3) in joint tissues. Following intra-articular injection of gal-3 or vehicle in knee joints of mice, histological evaluation of articular cartilage and subchondral bone was performed. Further studies were then performed using human osteoarthritic (OA) chondrocytes and subchondral bone osteoblasts, in which the effect of gal-3 (0 to 10 microg/ml) was analyzed. Osteoblasts were incubated in the presence of vitamin D3 (50 nM), which is an inducer of osteocalcin, encoded by an osteoblast terminal differentiation gene. Genes of interest mainly expressed in either chondrocytes or osteoblasts were analyzed with real-time RT-PCR and enzyme immunoassays. Signalling pathways regulating osteocalcin were analyzed in the presence of gal-3. Intra-articular injection of gal-3 induced knee swelling and lesions in both cartilage and subchondral bone. On human OA chondrocytes, gal-3 at 1 microg/ml stimulated ADAMTS-5 expression in chondrocytes and, at higher concentrations (5 and 10 microg/ml), matrix metalloproteinase-3 expression. Experiments performed with osteoblasts showed a weak but bipolar effect on alkaline phosphatase expression: stimulation at 1 microg/ml or inhibition at 10 microg/ml. In the absence of vitamin D3, type I collagen alpha 1 chain expression was inhibited by 10 microg/ml of gal-3. The vitamin D3 induced osteocalcin was strongly inhibited in a dose-dependent manner in the presence of gal-3, at both the mRNA and protein levels. This inhibition was mainly mediated by phosphatidylinositol-3-kinase. These findings indicate that high levels of extracellular gal-3, which could be encountered locally during the inflammatory process, have deleterious effects in both cartilage and subchondral bone tissues. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

13) Gatto CL, Walker BJ, Lambert S
Asymmetric ERM activation at the Schwann cell process tip is required in axon-associated motility.
J Cell Physiol. 2007 Jan;210(1):122-32.
Axon-associated Schwann cell (SC) motility and process dynamics are crucial in the development and regeneration of the peripheral nervous system (PNS). The bipolar morphology of SCs represents an unexplored conundrum in terms of directed motility. Using fluorescence time-lapse microscopy of transfected SCs within myelinating dorsal root ganglion (DRG) explants, we demonstrate cycling of SCs between bipolar and highly motile, unipolar morphologies as a result of asymmetric process retraction and extension. Unipolar SC motility appears nucleotaxic in nature, similar to the movement of neurons on radial glia during cortical development. We also show that asymmetric process retraction is associated with the activation of ERM (ezrin/radixin/moesin) proteins and subsequent recruitment of ezrin-binding phospho-protein 50 kDa (EBP50) at the retracting process tip. This activation occurs in response to localized synthesis of phosphatidylinositol (4,5)-bisphosphate (PIP2) at this site. Finally, we demonstrate that the activation of ERM proteins at the SC process tip is essential for motility and the maintenance of SC polarity, as ERM disruption yields a dysfunctional, multi-polar cell. These results demonstrate that specializations at the tips of SC processes regulate their dynamics, which in turn is associated with directed motility in these cells. [PubMed Citation] [Order full text from Infotrieve]

14) Billups D, Billups B, Challiss RA, Nahorski SR
Modulation of Gq-protein-coupled inositol trisphosphate and Ca2+ signaling by the membrane potential.
J Neurosci. 2006 Sep 27;26(39):9983-95.
Gq-protein-coupled receptors (GqPCRs) are widely distributed in the CNS and play fundamental roles in a variety of neuronal processes. Their activation results in phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis and Ca2+ release from intracellular stores via the phospholipase C (PLC)-inositol 1,4,5-trisphosphate (IP3) signaling pathway. Because early GqPCR signaling events occur at the plasma membrane of neurons, they might be influenced by changes in membrane potential. In this study, we use combined patch-clamp and imaging methods to investigate whether membrane potential changes can modulate GqPCR signaling in neurons. Our results demonstrate that GqPCR signaling in the human neuronal cell line SH-SY5Y and in rat cerebellar granule neurons is directly sensitive to changes in membrane potential, even in the absence of extracellular Ca2+. Depolarization has a bidirectional effect on GqPCR signaling, potentiating thapsigargin-sensitive Ca2+ responses to muscarinic receptor activation but attenuating those mediated by bradykinin receptors. The depolarization-evoked potentiation of the muscarinic signaling is graded, bipolar, non-inactivating, and with no apparent upper limit, ruling out traditional voltage-gated ion channels as the primary voltage sensors. Flash photolysis of caged IP3/GPIP2 (glycerophosphoryl-myo-inositol 4,5-bisphosphate) places the voltage sensor before the level of the Ca2+ store, and measurements using the fluorescent bioprobe eGFP-PH(PLCdelta) (enhanced green fluorescent protein-pleckstrin homology domain-PLCdelta) directly demonstrate that voltage affects muscarinic signaling at the level of the IP3 production pathway. The sensitivity of GqPCR IP3 signaling in neurons to voltage itself may represent a fundamental mechanism by which ionotropic signals can shape metabotropic receptor activity in neurons and influence processes such as synaptic plasticity in which the detection of coincident signals is crucial. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

15) McNamara RK, Ostrander M, Abplanalp W, Richtand NM, Benoit SC, Clegg DJ
Modulation of phosphoinositide-protein kinase C signal transduction by omega-3 fatty acids: implications for the pathophysiology and treatment of recurrent neuropsychiatric illness.
Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):237-57.
The phosphoinositide (PI)-protein kinase C (PKC) signal transduction pathway is initiated by pre- and postsynaptic Galphaq-coupled receptors, and regulates several clinically relevant neurochemical events, including neurotransmitter release efficacy, monoamine receptor function and trafficking, monoamine transporter function and trafficking, axonal myelination, and gene expression. Mounting evidence for PI-PKC signaling hyperactivity in the peripheral (platelets) and central (premortem and postmortem brain) tissues of patients with schizophrenia, bipolar disorder, and major depressive disorder, coupled with evidence that PI-PKC signal transduction is down-regulated in rat brain following chronic, but not acute, treatment with antipsychotic, mood-stabilizer, and antidepressant medications, suggest that PI-PKC hyperactivity is central to an underlying pathophysiology. Evidence that membrane omega-3 fatty acids act as endogenous antagonists of the PI-PKC signal transduction pathway, coupled with evidence that omega-3 fatty acid deficiency is observed in peripheral and central tissues of patients with schizophrenia, bipolar disorder, and major depressive disorder, support the hypothesis that omega-3 fatty acid deficiency may contribute to elevated PI-PKC activity in these illnesses. The data reviewed in this paper outline a potential molecular mechanism by which omega-3 fatty acids could contribute to the pathophysiology and treatment of recurrent neuropsychiatric illness. [PubMed Citation] [Order full text from Infotrieve]

16) M�rmol F
[Lithium: 55 years of history in the therapy of bipolar affective disorder]
Med Clin (Barc). 2006 Jul 1;127(5):189-95.
The clinical history of lithium began in mid-19th century when it was used to treat gout. It was subsequently administered as a substitute for sodium chloride and towards the end of 1940 its effects for the control of mania were discovered. At present it is used effectively for treatment of mania and for the prophylaxis of bipolar disorder. Though its effect on affective illnesses is evident, the same cannot be said of its mechanism of action, since in spite of the numerous studies performed to date it is still not known exactly how this ion acts. Many theories have been proposed, the most important of which are: normalisation of possible ionic alterations; interactions with the adenylyl cyclase cAMP system; effects on the phosphatidylinositol cycle; stabilisation of the levels of neuroprotective proteins; normalisation of the values of some cytosolic endopeptidases; etc. In any case, it has yet to be determined which of these is the principal factor responsible for lithium's therapeutic action, while at the same time the possibility cannot be totally ruled out that its precise mechanism of action is still to be discovered. [PubMed Citation] [Order full text from Infotrieve]

17) Jamra RA, Klein K, Villela AW, Becker T, Schulze TG, Schmael C, Deschner M, Klopp N, Illig T, Propping P, Cichon S, Rietschel M, N�then MM, Schumacher J
Association study between genetic variants at the PIP5K2A gene locus and schizophrenia and bipolar affective disorder.
Am J Med Genet B Neuropsychiatr Genet. 2006 Sep 5;141B(6):663-5.
Results from molecular and pharmacological studies point to involvement of the gene coding for the phosphatidylinositol-4-phosphate 5-kinase type II-alpha (PIP5K2A) in the development of schizophrenia and bipolar affective disorder (BPAD). The PIP5K2A gene locus, which is located on chromosomal region 10p12, has been implicated in the development of both disorders by independent linkage and association studies. On a cellular level, PIP5K2A is an enzyme component of the metabolism of inositol phosphate, which has been considered a potential target for the therapeutic action of lithium in BPAD patients. Given that the PIP5K2A gene is a promising candidate for the development of both disorders, we performed an association study between genetic variants at the PIP5K2A locus and 268 patients with schizophrenia, 260 patients with BPAD and 325 ethnically matched healthy controls. We failed to detect association to either disorder using PIP5K2A gene variants through single-marker and haplotype analysis. Therefore, our data does not support an involvement of the PIP5K2A locus in the etiology of either schizophrenia or BPAD in the German population. [PubMed Citation] [Order full text from Infotrieve]

18) Sun X, Wang JF, Tseng M, Young LT
Downregulation in components of the mitochondrial electron transport chain in the postmortem frontal cortex of subjects with bipolar disorder.
J Psychiatry Neurosci. 2006 May;31(3):189-96.
OBJECTIVE: Many studies indicate a genetic predisposition to bipolar disorder (BD) and suggest that a number of abnormal genes are involved in its development. In this study, we used DNA microarray technology to analyze gene-expression profiles in the postmortem frontal cortex of subjects with BD. METHODS: Microarray hybridization was performed using human 19K microarray with universal human reference RNA in each hybridization. The reference cDNA was labelled with Cy3 and experimental cDNA, with Cy5. Glass array slides were cohybridized with equal amounts of mixed reference and experimental cDNA. Selected gene targets were further verified using real-time polymerase chain reaction (PCR). RESULTS: We found that 831 genes were differentially expressed in subjects with BD, including a number of genes in the mitochondrial electron transport chain (ETC), phosphatidylinositol-signalling system and glycolysis/ gluconeogenesis. Eight genes coding for the components of the mitochondrial ETC were identified along with 15 others related to mitochondrial function. Downregulation of NADH-ubiquinone oxidoreductase 20-kd subunit (ETC complex I), cytochrome c oxidase polypeptide Vic (ETC complex IV) and ATP synthase lipid-binding protein (ETC complex V) were further verified by real-time PCR. We also found that the expression of the NADH-ubiquinone oxidoreductase 20-kd subunit was increased in subjects with BD who were receiving mood-stabilizing treatment with lithium at the time of death, when compared with subjects with BD who were not being treated with lithium. CONCLUSIONS: Because the mitochondrial ETC is a major source for the generation of reactive oxygen species, these findings suggest that oxidative damage may play an important role in the pathophysiology of BD and that neuroprotection against this damage may be involved in the effect of lithium treatment. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

19) Shaldubina A, Johanson RA, O'Brien WT, Buccafusca R, Agam G, Belmaker RH, Klein PS, Bersudsky Y, Berry GT
SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior.
Mol Genet Metab. 2006 Aug;88(4):384-8.
Two leading hypotheses to explain lithium action in bipolar disorder propose either inositol depletion or inhibition of GSK-3 as mechanisms of action. Behavioral effects of lithium are mimicked in Gsk-3beta+/- mice, but the contribution of inositol depletion to these behaviors has not been tested. According to the inositol depletion hypothesis, lithium-sensitive behavior is secondary to impaired phosphatidylinositol synthesis caused by inositol deficiency. By disrupting the sodium myo-inositol transporter1 gene, SMIT1, we show that depletion of brain myo-inositol in SMIT1+/- mice has no effect on lithium-sensitive behavior. These findings, taken together with our previous work showing that SMIT-/- mice have an even greater depletion of inositol in brain with no reduction in phosphatidylinositol levels, are difficult to reconcile with the current formulation of the inositol depletion hypothesis. [PubMed Citation] [Order full text from Infotrieve]

20) Bosson R, Jaquenoud M, Conzelmann A
GUP1 of Saccharomyces cerevisiae encodes an O-acyltransferase involved in remodeling of the GPI anchor.
Mol Biol Cell. 2006 Jun;17(6):2636-45.
The anchors of mature glycosylphosphatidylinositol (GPI)-anchored proteins of Saccharomyces cerevisiae contain either ceramide or diacylglycerol with a C26:0 fatty acid in the sn2 position. The primary GPI lipid added to newly synthesized proteins in the ER consists of diacylglycerol with conventional C16 and C18 fatty acids. Here we show that GUP1 is essential for the synthesis of the C26:0-containing diacylglycerol anchors. Gup1p is an ER membrane protein with multiple membrane-spanning domains harboring a motif that is characteristic of membrane-bound O-acyl-transferases (MBOAT). Gup1Delta cells make normal amounts of GPI proteins but most mature GPI anchors contain lyso-phosphatidylinositol, and others possess phosphatidylinositol with conventional C16 and C18 fatty acids. The incorporation of the normal ceramides into the anchors is also disturbed. As a consequence, the ER-to-Golgi transport of the GPI protein Gas1p is slow, and mature Gas1p is lost from the plasma membrane into the medium. Gup1Delta cells have fragile cell walls and a defect in bipolar bud site selection. GUP1 function depends on the active site histidine of the MBOAT motif. GUP1 is highly conserved among fungi and protozoa and the gup1Delta phenotype is partially corrected by GUP1 homologues of Aspergillus fumigatus and Trypanosoma cruzi. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]