[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.
(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]
JC, Mallinger AG, Dippold CS, Frank E, Kupfer DJ.
phospholipids in euthymic bipolar disorder patients: are they affected by lithium
Biol Psychiatry. 1999 Feb 15;45(4):453-7.
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]
JC, Chen G, Dippold CS, Wells KF, Frank E, Kupfer DJ, Manji HK, Mallinger AG.
measures of protein kinase C and phosphoinositides in lithium-treated bipolar
patients and healthy individuals: a preliminary study.
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]
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
"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]
E, Lerer B, Newman ME.
Acute or chronic lithium does not affect agonist-stimulated
inositol trisphosphate formation in rat brain in vivo.
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]
Y, Fujimagari M, Masuzawa Y, Waku K.
accumulation in brain of lithium-treated rats.
"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.
screening of PIP5K2A: a candidate gene for chromosome 10p-linked psychiatric disorders.
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.
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]
JC, Dippold CS, Mallinger AG.
Platelet membrane phosphatidylinositol-4,5-bisphosphate
alterations in bipolar disorder--evidence from a single case study.
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]
AS, Mallinger AG, Renbaum LC.
Elevated platelet membrane phosphatidylinositol-4,5-bisphosphate
in bipolar mania.
Am J Psychiatry. 1993 Aug;150(8):1252-4.
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."
LK, Seelan RS, Wilson MA, Vadnal RE, Parthasarathy RN.
in rat brain inositol monophosphatase 1 (IMPase 1) activity with chronic lithium
Prog Neuropsychopharmacol Biol Psychiatry. 2003
"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,
Examination of IMPA1 and IMPA2 genes in manic-depressive
patients: association between IMPA2 promoter polymorphisms and bipolar disorder.
Psychiatry. 2003 Dec 23 [Epub ahead of print].
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."
R, Parthasarathy R.
Myo-inositol monophosphatase: diverse effects
of lithium, carbamazepine, and valproate.
"The therapeutic molecular sites of action for
the mood-stabilizing medications are unknown. Myo-inositol monophosphatase (E.C.
220.127.116.11) 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."
José M. López-Coronado, José M. Bellés,
Florian Lesage, Ramón Serrano, and Pedro L. Rodríguez
Novel Mammalian Lithium-sensitive Enzyme with a Dual Enzymatic Activity, 3'-Phosphoadenosine
5'-Phosphate Phosphatase and Inositol-polyphosphate 1-Phosphatase
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]