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Manji HK, Chen G.
PKC, MAP kinases and the bcl-2
family of proteins as long-term targets for mood stabilizers.
Mol
Psychiatry 2002;7 Suppl 1:S46-56
"The complexity of the unique biology
of bipolar disorder--which includes the predisposition to episodic, and often
progressive, mood disturbance--and the dynamic nature of compensatory processes
in the brain, coupled with limitations in experimental design, have hindered our
ability to identify the underlying pathophysiology of this fascinating neuropsychiatric
disorder. Although we have yet to identify the specific abnormal genes in mood
disorders, recent studies have implicated critical signal transduction pathways
as being integral to the pathophysiology and treatment of bipolar disorder. In
particular, a converging body of preclinical data has shown that chronic lithium
and valproate, at therapeutically relevant concentrations, regulate the protein
kinase C signaling cascade. This has led to the investigation of the antimanic
efficacy of tamoxifen (at doses sufficient to inhibit protein kinase C), with
very encouraging preliminary results. A growing body of data also suggests that
impairments of neuroplasticity and cellular resilience may also underlie the pathophysiology
of bipolar disorder. It is thus noteworthy that mood stabilizers, such as lithium
and valproate, indirectly regulate a number of factors involved in cell survival
pathways--including cAMP response element binding protein, brain derived neurotrophic
factor, bcl-2 and mitogen-activated protein kinases--and may thus bring about
some of their delayed long-term beneficial effects via under-appreciated neurotrophic
effects. The development of novel treatments, which more directly target molecules
involved in critical central nervous system cell survival and cell death pathways,
has the potential to enhance neuroplasticity and cellular resilience, thereby
modulating the long-term course and trajectory of these devastating illnesses."
[Abstract] Wang
HY, Johnson GP, Friedman E.
Lithium treatment inhibits protein kinase
C translocation in rat brain cortex.
Psychopharmacology
(Berl) 2001 Oct;158(1):80-6
"RATIONALE: Lithium, an effective psychotropic
agent, affects membrane phospholipid metabolism, interferes with phosphoinositide
signal transduction, and antagonizes the biological activity of calcium, all major
factors of protein kinase C (PKC) activation. Consequently, lithium may interfere
with cellular functions requiring PKC. Supporting this hypothesis, lithium was
found to inhibit increased neurotransmitter release upon PKC activation and to
prevent phorbol ester-mediated PKC translocation. OBJECTIVES: The present study
was undertaken to determine whether the frontal cortex of rats treated with lithium
exhibits altered PKC activity and translocation in response to phorbol ester,
K+, or serotonin (5-HT) receptor stimulation and to determine whether specific
PKC isozymes are disproportionately affected. METHODS: Rats were fed either a
normal diet or one enriched with LiCl. In cerebrocortical slices or synaptosomes,
cytosolic and membranous PKC activity and translocation in response to stimuli
were determined after partial purification with anion exchange chromatography.
RESULTS: In brain slices, lithium treatment inhibited phorbol 12-myristate, 13-acetate
(PMA)-, 5-HT-, or K+-induced PKC translocation from cytosol to membrane without
affecting basal membrane or cytosolic PKC activity. In synaptosomes, lithium also
attenuated PMA- or K+-evoked translocation of PKC. Immunoblotting with isozyme-specific
PKC antibodies revealed that chronic lithium treatment reduced basal cytosolic
alphaPKC and deltaPKC but increased membrane-associated zetaPKC immunoreactivities.
Stimulation with PMA, 5-HT or K+ elicited translocation of alpha, beta and gammaPKC
isozymes and PMA induced translocation of delta and epsilonPKC isozymes. Stimulus-mediated
translocation of PKC isozymes was attenuated in cortical tissue obtained from
animals that received lithium for 6 weeks. In synaptosomes, PMA- or K+-induced
PKC translocation was attenuated by in vitro lithium or chronic lithium treatment.
Neither rubidium nor cesium affected PKC activities or PMA-induced translocation.
Suppression of PMA-elicited translocation by lithium was partially antagonized
by Ca2+. CONCLUSIONS: Lithium treatment reduces PKC translocation induced by either
stimulation of a cell surface receptor or by direct enzyme stimulation with phorbol
ester. This effect leads to reduced PKC-mediated phosphorylation of cellular proteins
and may be responsible for the pharmacotherapeutic action of lithium." [Abstract] Chen,
G, Manji, HK, Hawver, DB, Wright, CB, Potter, WZ
Chronic sodium
valproate selectively decreases protein kinase C alpha and epsilon in vitro
J Neurochem 1994 63: 2361-2364
"Valproic acid (VPA) is
a fatty acid antiepileptic with demonstrated antimanic properties, but the molecular
mechanism or mechanisms underlying its therapeutic efficacy remain to be elucidated.
In view of the increasing evidence demonstrating effects of the first-line antimanic
drug, lithium, on protein kinase C (PKC), we investigated the effects of VPA on
various aspects of this enzyme. Chronic exposure (6-7 days) of rat C6 glioma cells
to "therapeutic" concentrations (0.6 mM) of VPA resulted in decreased
PKC activity in both membrane and cytosolic fractions and increased the cytosol/membrane
ratio of PKC activity. Western blot analysis revealed isozyme-selective decreases
in the levels of PKC alpha and epsilon (but not delta or zeta) in both the membrane
and cytosolic fractions after chronic VPA exposure; VPA added to reaction mixtures
did not alter PKC activity or 3H-phorbol ester binding. Together, these data suggest
that chronic VPA indirectly lowers the levels of specific isozymes of PKC in C6
cells. Given the pivotal role of PKC in regulating neuronal signal transduction
and modulating intracellular cross-talk between neurotransmitter systems, the
specific decreases in PKC alpha and epsilon may play a role in the antimanic effects
of VPA." [Abstract]
Anna M. Rice, and Alan C. Sartorelli
Inhibition
of 20 S and 26 S Proteasome Activity by Lithium Chloride. IMPACT
ON THE DIFFERENTIATION OF LEUKEMIA CELLS BY ALL-TRANS-RETINOIC ACID
J. Biol. Chem. 276: 42722-42727, November 16, 2001.
"Cleavage
of the peptide substrate Suc-Leu-Leu-Val-Leu-AMC by the 20 S proteasome in the
presence of 0.035% SDS resulted in fluorescence at 460 nm. 20 S proteasomes from
WEHI-3B D+ cells displayed activity similar to that of commercially available
rabbit 20 S proteasomes (>95% purity) (Fig. 2A). The presence of increasing
concentrations of LiCl decreased the rate of chymotryptic activity of WEHI-3B
D+ and rabbit 20 S proteasomes (Fig. 2, B and C). LiCl at 2.5 mM significantly
reduced peptide cleavage after 1 h by WEHI-3B D+ 20 S proteasomes, whereas 10
mM LiCl reduced fluorescence in this system to background levels." "No
effect was observed on 20 S proteasome activity by the presence of 1-5 mM NaCl
(Fig. 3A); however, 10 mM NaCl decreased activity slightly. In contrast, neither
KCl nor ATRA significantly affected the rate of chymotryptic-like activity of
20 S proteasomes (Fig. 3, B and C). These observations suggest that LiCl has a
unique effect on both WEHI-3B D+ and rabbit proteasome activity, and that this
inhibitory effect probably is responsible for the observed accumulation of polyubiquitinated
RAR species following exposure of WEHI-3B D+ cells to LiCl." [Full
Text] Yamada S, Hojo K, Yoshimura H, Ishikawa
K.
Reaction of 20S proteasome: shift of SDS-dependent activation
profile by divalent cations.
J Biochem (Tokyo) 1995 Jun;117(6):1162-9
"This study examined the effects of various divalent cations on the SDS-dependent
peptidase and casein degradation activities of 20S proteasome purified from Xenopus
laevis oocytes at a series of SDS concentrations and the correlation between these
effects and the critical micelle concentration (CMC) of SDS. Surprisingly, it
was found that divalent cations such as Mg2+ markedly shifted the SDS-dependent
activation profiles to a lower concentration range." [Abstract] Ishiura
S, Nojima M, Yamamoto T, Fuchiwaki T, Okuyama T, Furuya H, Sugita H.
Effects
of linoleic acid and cations on the activity of a novel high-molecular weight
protease, ingensin, from human placenta.
Int J Biochem
1986;18(9):765-9
"A linoleic acid-sensitive protease, ingensin, was purified
to homogeneity from human placenta. The physical properties of the placental ingensin
were found to be very similar to those of skeletal muscle ingensin [Ishiura et
al. (1985) FEBS Lett. 189, 119-123]. The purified ingensin was activated by linoleic
acid and SDS. The linoleic acid-activated form was inhibited preferentially by
divalent cations, whereas the SDS-activated form was inhibited by monovalent cations
instead."
[Abstract] Fischer
M, Hilt W, Richter-Ruoff B, Gonen H, Ciechanover A, Wolf DH.
The
26S proteasome of the yeast Saccharomyces cerevisiae.
FEBS
Lett 1994 Nov 21;355(1):69-75
"20S proteasomes have been found in all
eukaryotes from yeast to man. So far 26S proteasomes have only been discovered
in higher eukaryotes. We now report the existence of the 26S proteasome in a lower
eukaryote, the yeast Saccharomyces cerevisiae. Formation of the 26S proteasome
could most effectively be induced in crude extracts of heat stressed yeast cells
by incubation with ATP and Mg2+ ions." [Abstract] Abukhdeir
AM, Layden BT, Minadeo N, Bryant FB, Stubbs EB Jr, Mota de Freitas D.
Effect
of chronic Li+ treatment on free intracellular Mg2+ in human neuroblastoma SH-SY5Y
cells.
Bipolar Disord. 2003 Feb;5(1):6-13.
"OBJECTIVES:
Previous findings have demonstrated Li+/Mg2+ competition at therapeutic intracellular
Li+ levels after acute Li+ treatment in human neuroblastoma SH-SY5Y cells. In
the current study, we examined whether Li+/Mg2+ competition exists at therapeutically
relevant extra- and intracellular [Li+] after chronic Li+ loading times. METHODS:
In human neuroblastoma cells, intracellular free Mg2+ was determined by fluorescence
spectroscopy with the fluorophore furaptra. Intracellular Li+ and Mg2+ were measured
by atomic absorption spectrophotometry. RESULTS: After loading of the neuroblastoma
cells with 1-2 mM extracellular Li+ for 24-72 h, the observed, increased intracellular
free [Mg2+] levels were significantly higher (p < 0.03) than those in matched
Li+ free cells, and intracellular [Li+] was found to be at therapeutic intracellular
levels (0.7-1.5 mM). CONCLUSIONS: The results demonstrate that Li+/Mg2+ competition
exists after chronic treatment with Li+ at therapeutically relevant intracellular
Li+ levels in neuroblastoma cells. We found differences between acute and chronic
Li+ treatment effects on the extent of Li+/Mg2+ competition. Possible reasons
for these differences are discussed." [Abstract] Amari,
Louis, Layden, Brian, Nikolakopoulos, Joyce, Rong, Qinfen, Mota de Freitas, Duarte,
Baltazar, Graca, Castro, M. Margarida C. A., Geraldes, Carlos F. G. C.
Competition between Li+ and Mg2+ in Neuroblastoma SH-SY5Y Cells: A Fluorescence
and 31P NMR Study
Biophys. J. 1999 76: 2934-2942
"Because
Mg2+ and Li+ ions have similar chemical properties, we have hypothesized that
Li+/Mg2+ competition for Mg2+ binding sites is the molecular basis for the therapeutic
action of lithium in manic-depressive illness. By fluorescence spectroscopy with
furaptra-loaded cells, the free intracellular Mg2+ concentration within the intact
neuroblastoma cells was found to increase from 0.39 ± 0.04 mM to 0.60 ±
0.04 mM during a 40-min Li+ incubation in which the total intracellular Li+ concentration
increased from 0 to 5.5 mM. Our fluorescence microscopy observations of Li+-free
and Li+-loaded cells also indicate an increase in free Mg2+ concentration upon
Li+ incubation. By 31P NMR, the free intracellular Mg2+ concentrations for Li+-free
cells was 0.35 ± 0.03 mM and 0.80 ± 0.04 mM for Li+-loaded cells
(final total intracellular Li+ concentration of 16 mM). If a Li+/Mg2+ competition
mechanism is present in neuroblastoma cells, an increase in the total intracellular
Li+ concentration is expected to result in an increase in the free intracellular
Mg2+ concentration, because Li+ displaces Mg2+ from its binding sites within the
nerve cell. The fluorescence spectroscopy, fluorescence microscopy, and 31P NMR
spectroscopy studies presented here have shown this to be the case." [Full
Text]
Rick A. Finch, Jianming Li, T-C. Chou,
and Alan C. Sartorelli
Maintenance of retinoic acid receptor alpha
pools by granulocyte colony-stimulating factor and lithium chloride in all-trans
retinoic acid-treated WEHI-3B leukemia cells: relevance to the synergistic induction
of terminal differentiation
Blood 96: 2262-2268, September
2000.
"Interestingly, both G-CSF and LiCl were capable of protecting
RAR pools in ATRA-treated cells by what appeared to be a nontranscriptional mechanism
while producing synergistic terminal differentiation of the leukemia cells."
[Full
Text] Yuan, Peixiong, Chen, Guang, Manji, Husseini
K.
Lithium Activates the c-Jun NH2-Terminal Kinases In Vitro and
in the CNS In Vivo
J Neurochem 1999 73: 2299-2309
"Lithium
also increased cJun-mediated reporter gene expression in a dose-dependent manner,
with significant effects observed at therapeutically relevant concentrations.
Lithium's effects on cJun-mediated reporter gene expression in SH-SY5Y cells were
more pronounced in the absence of myo-inositol and were blocked by protein kinase
C (PKC) inhibitors and by cotransfection with a PKC alpha dominant-negative mutant."
"It is quite likely that
the initial lithium-induced PKC activation may result in increased AP-1 DNA binding
activity, which persists even after the down-regulation of PKC alpha and epsilon.
Indeed, evidence from various sources has shown that long-term neuronal changes
can be maintained by effectors that themselves only transiently maintain the active
conformation." [Abstract]
Coleman ES, Wooten MW.
Nerve
growth factor-induced differentiation of PC12 cells employs the PMA-insensitive
protein kinase C-zeta isoform.
J Mol Neurosci 1994 Spring;5(1):39-57
"To
elucidate the role of protein kinase C (PKC) in nerve growth factor (NGF)-induced
differentiation, PMA downregulation of pheochromocytoma (PC12) cells was undertaken.
Prolonged treatment (2 d) of PC12 cells with PMA (1 microM) resulted in depleting
the cells of alpha, beta, delta, and epsilon-PKC isoforms, but had no effect on
the expression of the atypical PKC isoform zeta." [Abstract]
[Note that PMA is a PKC activator.] Cho Y, Tighe
AP, Talmage DA.
Retinoic acid induced growth arrest of human breast
carcinoma cells requires protein kinase C alpha expression and activity.
J
Cell Physiol 1997 Sep;172(3):306-13
"Retinoic acid inhibits proliferation
of hormone-dependent, but not hormone-independent breast cancer cells. Retinoic
acid-induced changes in cellular proliferation and differentiation are associated
with disturbances in growth factor signaling and frequently with changes in protein
kinase C expression. PKC delta, epsilon, and zeta are expressed in both hormone-dependent
(T-47D) and hormone-independent (MDA-MB-231) cell lines. Retinoic acid arrested
T-47D proliferation, induced PKC alpha expression and concomitantly repressed
PKC zeta expression. The changes in PKC alpha and PKC zeta reflect retinoic acid-induced
changes in mRNA. In contrast, retinoic acid had no effect on growth, or PKC expression
in MDA-MB-231 cells. Growth arrest and the induction of PKC alpha, but not the
reduction in PKC zeta, resulted from selective activation of RAR alpha. In total,
these results support an important role for PKC alpha in mediating the anti-proliferative
action of retinoids on human breast carcinoma cells." [Abstract] Cho
Y, Talmage DA.
Protein kinase Calpha expression confers retinoic
acid sensitivity on MDA-MB-231 human breast cancer cells.
Exp
Cell Res 2001 Sep 10;269(1):97-108
"Retinoic acid activation of retinoic
acid receptor alpha (RARalpha) induces protein kinase Calpha (PKCalpha) expression
and inhibits proliferation of the hormone-dependent T-47D breast cancer cell line.
Retinoic acid has no effect on proliferation or PKCalpha expression in a hormone-independent,
breast cancer cell line (MDA-MB-231). To test the role of PKCalpha in retinoic
acid-induced growth arrest of human breast cancer cells we established MDA-MB-231
cell lines stably expressing PKCalpha. Constitutive expression of PKCalpha did
not affect proliferation of MDA-MB-231 cells but did result in partial retinoic
acid sensitivity. Retinoic acid treatment of PKCalpha-MDA-MB-231 cells decreased
proliferation (by approximately 40%) and inhibited serum activation of MAP kinases
and induction of c-fos. Similar results were seen in MDA-MB-231 cells in which
transcription of the transfected PKCalpha cDNA was reversibly induced by isopropyl
beta-d-thiogalactoside. Expression of RARalpha in PKCalpha expressing MDA-MB-231
cells resulted in even greater retinoic acid responses, as measured by effects
on cell proliferation, inhibition of serum signaling, and transactivation of an
RARE-CAT reporter plasmid. In summary, PKCalpha synergizes with activated RARalpha
to disrupt serum growth factor signaling, ultimately arresting proliferation of
MDA-MB-231 cells." [Abstract]
... Anna Radominska-Pandya, Guangping Chen,
Piotr J. Czernik, Joanna M. Little, Victor M. Samokyszyn, Charleata A. Carter,
and Graz·yna Nowak
Direct Interaction of All-trans-retinoic
Acid with Protein Kinase C (PKC). IMPLICATIONS FOR PKC SIGNALING
AND CANCER THERAPY
J. Biol. Chem. 275: 22324-22330,
July 2000.
"These results let us hypothesize that in vivo, pharmacological
concentrations of atRA may hamper binding of PS to PKC alpha and prevent PKC alpha
activation." [Full
Text] Watson DG, Wainer BH, Lenox RH.
Phorbol ester- and retinoic acid-induced regulation of the protein kinase C
substrate MARCKS in immortalized hippocampal cells.
J Neurochem
1994 Nov;63(5):1666-74
"MARCKS protein expression was also down-regulated
in a dose-dependent manner on exposure of HN33 cells to retinoic acid." [Abstract] Chen
M, Antoni L, Tazi-Ahnini R, Cork M, Ward S, Bavik C.
Identification
of known and novel genes whose expression is regulated by endogenous retinoic
acid during early embryonic development of the mouse.
Mech
Dev 2002 Jun;114(1-2):205
"The utility of the method is exemplified by
our finding that several genes in the Wnt signaling pathway are vitamin A regulated
in day 9.0 post coitum (p.c.) embryos." [Abstract] Mora
A, Sabio G, Risco AM, Cuenda A, Alonso JC, Soler G, Centeno F.
Lithium
blocks the PKB and GSK3 dephosphorylation induced by ceramide through protein
phosphatase-2A.
Cell Signal 2002 Jun;14(6):557-62
"Since
lithium inhibits in vivo the observed protein phosphatase-2A (PP2A) activation
induced by ceramide, we hypothesise that the neuroprotective action of lithium
may be due to the inhibition of the PP2A activation by apoptotic stimuli."
[Abstract] Galadari
S, Hago A, Patel M.
Effects of cations on ceramide-activated protein
phosphatase 2A.
Exp Mol Med 2001 Dec 31;33(4):240-4
"In this study, we investigated the effects of metal ions and chelators on
ceramide-activated PP2A (CAPP). Our study demonstrates that at 0.5 mM concentration,
Mg2+ appears to have no significant effect on either basal or ceramide-stimulated
phosphatase activities, whereas Ca2+ stimulated the basal phosphatase activity,
but was inhibitory towards CAPP. Moreover, the divalent cations Cr2+, Mn2+, Fe2+,
Ni2+, Cu2+ and Zn2+ were tested and all were found to be inhibitory towards both
CAPP and basal phosphatase activities. By contrast, Cs+ and Li+ had almost no
effect on CAPP, although both stimulated basal phosphatase activity." [Abstract] I
Tawara, M Nishikawa, K Morita, K Kobayashi, H Toyoda, SB Omay, H Shima, M Nagao,
T Kuno, and C Tanaka
Down-regulation by retinoic acid of the catalytic
subunit of protein phosphatase type 2A during granulocytic differentiation of
HL-60 cells.
FEBS Lett, Apr 1993; 321(2-3): 224-8.
"The decreased phosphatase activity may be mainly due to a decrease in the
expression of the PP2A protein. The mRNA level of PP2A beta was markedly decreased
within 5 h after addition of ATRA, but there was only a slight increase in the
mRNA level of PP2A alpha. Selective down-regulation of PP2A beta mRNA clearly
preceded the cell differentiation induced by ATRA treatment. Thus, PP2A is down-regulated
during ATRA-induced differentiation of HL-60 cells into granulocytes." [Abstract] Ruvolo
PP, Clark W, Mumby M, Gao F, May WS.
A functional role for the B56
alpha-subunit of protein phosphatase 2A in ceramide-mediated regulation of Bcl2
phosphorylation status and function.
J Biol Chem 2002 Jun
21;277(25):22847-52
"Recently it has been shown that the potent apoptotic
agent ceramide activates a mitochondrial protein phosphatase 2A (PP2A) and promotes
dephosphorylation of the anti-apoptotic molecule Bcl2 (Ruvolo, P. P., Deng, X.,
Ito, T., Carr, B. K., and May, W. S. (1999) J. Biol. Chem. 274, 20296-20300).
In cells expressing Bcl2, dephosphorylation of Bcl2 appears to be required for
ceramide-induced cell death because treatment of cells with low doses of the PP2A
inhibitor okadaic acid blocks Bcl2 dephosphorylation and promotes cell survival."
[Abstract] Dimmeler,
Stefanie, Breitschopf, Kristin, Haendeler, Judith, Zeiher, Andreas M.
Dephosphorylation Targets Bcl-2 for Ubiquitin-dependent Degradation: A Link
between the Apoptosome and the Proteasome Pathway
J. Exp.
Med. 1999 189: 1815-1822
"Finally, inhibition of Bcl-2 degradation either
by suppressing ubiquitin-dependent proteasomal degradation or by mimicking continuous
phosphorylation of the putative MAP kinase sites in the Bcl-2 protein confers
resistance against induction of apoptosis." [Full
Text] Jiandi Zhang, Nejemie Alter, John C. Reed,
Christoph Borner, Lina M. Obeid, and Yusuf A. Hannun
Bcl-2 interrupts
the ceramide-mediated pathway of cell death
PNAS 93: 5325-5328,
May 1996.
"Overexpression of bcl-2 prevented apoptosis in response
to ceramide, suggesting that bcl-2 acts at a point downstream of ceramide."
[Abstract/Full Text]
M Lam, G Dubyak, L Chen, G Nunez, RL Miesfeld, and CW Distelhorst
Evidence that BCL-2 Represses Apoptosis by Regulating Endoplasmic
Reticulum-Associated Ca2+ Fluxes
PNAS 91: 6569-6573, 1994.
"By reducing ER Ca2+ efflux, BCL-2 interfered with a signal for "capacitative"
entry of extracellular Ca2+, preventing a sustained increase of cytosolic Ca2+
in TG-treated cells. These findings suggest that BCL-2 either directly or indirectly
regulates the flux of Ca2+ across the ER membrane, thereby abrogating Ca2+ signaling
of apoptosis." [Article] Peter
P. Ruvolo, Xingming Deng, Boyd K. Carr, and W. Stratford May
A
Functional Role for Mitochondrial Protein Kinase C in Bcl2 Phosphorylation and
Suppression of Apoptosis
J. Biol. Chem. 273: 25436-25442,
September 1998.
"Thus, if it can be demonstrated that the chemotherapy-resistant
leukemic cells also contain relatively high levels of mitochondrial PKC alpha
and phosphorylated Bcl2, one novel therapeutic strategy for translational research
might involve the selective inhibition of PKC alpha and blockade of Bcl2 phosphorylation
prior to institution of induction-remission chemotherapy." [Full
Text] Bosetti F, Seemann R, Rapoport SI.
Chronic
lithium chloride administration to rats decreases brain protein level of epsilon
(epsilon) subunit of eukaryotic initiation factor-2B.
Neurosci
Lett 2002 Jul 12;327(1):71-3
"The eukaryotic initiation factor-2B (eIF-2B)
can regulate translation and protein synthesis. We used Western blot analysis
to quantify the protein level of the catalytic epsilon (epsilon) subunit of eIF-2B
in brains of rats fed lithium chloride (LiCl) for 6 weeks so as to produce a brain
lithium concentration that is therapeutically effective in bipolar disorder. The
ratio of eIF-2B (epsilon) to actin protein was significantly reduced (P<0.01)
in LiCl-fed rats, 0.86+/-0.06 (SE) compared to 1.2+/-0.07 in control rats. These
results suggest that a therapeutic level of lithium may downregulate the synthesis
of proteins whose translation depends on eIF-2B." [Abstract] Xingming
Deng, Lei Xiao, Wenhua Lang, Fengqin Gao, Peter Ruvolo, and W. Stratford May,
Jr.
Novel Role for JNK as a Stress-activated Bcl2 Kinase
J. Biol. Chem. 276: 23681-23688, June 2001.
Furthermore, low
dose okadaic acid (OA), a potent protein phosphatase 1 and 2A inhibitor, can activate
the mitogen-activated protein kinases JNK1 and ERK1/2, but not p38 kinase, to
induce Bcl2 phosphorylation and prolong cell survival in factor-deprived cells.
[Full Text]
Bosetti
F, Rintala J, Seemann R, Rosenberger TA, Contreras MA, Rapoport SI, Chang MC.
Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E(2)
concentration in rat brain.
Mol Psychiatry 2002;7(8):845-50
"Rats treated with lithium chloride for 6 weeks have been reported to demonstrate
reduced turnover of arachidonic acid (AA) in brain phospholipids, and decreases
in mRNA and protein levels, and enzyme activity, of AA-selective cytosolic phospholipase
A(2)(cPLA(2)). We now report that chronic lithium administration to rats significantly
reduced the brain protein level and enzyme activity of cyclooxygenase-2 (COX-2),
without affecting COX-2 mRNA. Lithium also reduced the brain concentration of
prostaglandin E(2) (PGE(2)), a bioactive product of AA formed via the COX reaction.
COX-1 and the Ca(2+)-independent iPLA(2) (type VI) were unaffected by lithium.
These and prior results indicate that lithium targets a part of the AA cascade
that involves cPLA(2) and COX-2. This effect may contribute to lithium's therapeutic
action in bipolar disorder."
[Abstract] Chang
MC, Contreras MA, Rosenberger TA, Rintala JJ, Bell JM, Rapoport SI.
Chronic valproate treatment decreases the in vivo turnover of arachidonic acid
in brain phospholipids: a possible common effect of mood stabilizers.
J Neurochem 2001 May;77(3):796-803
"Both (Li(+)) and valproic acid (VPA)
are effective in treating bipolar disorder, but the pathway by which either works,
and whether it is common to both drugs, is not agreed upon. We recently reported,
using an in vivo fatty acid model, that Li(+) reduces the turnover rate of the
second messenger arachidonic acid (AA) by 80% in brain phospholipids of the awake
rat, without changing turnover rates of docosahexaenoic or palmitic acid. Reduced
AA turnover was accompanied by down-regulation of gene expression and protein
levels of an AA-specific cytosolic phospholipase A(2) (cPLA(2)). To see if VPA
had the same effect on AA turnover, we used our in vivo fatty acid model in rats
chronically administered VPA (200 mg/kg, i.p. for 30 days). Like Li(+), VPA treatment
significantly decreased AA turnover within brain phospholipids (by 28-33%), although
it had no effect on cPLA(2) protein levels. Thus, both mood stabilizers, Li(+)
and VPA have a common action in reducing AA turnover in brain phospholipids, albeit
by different mechanisms." [Abstract] Weerasinghe
GR, Seemann R, Rapoport SI, Bosetti F.
Lithium chloride, administered
chronically to rats, does not affect the fractional phosphorylation of brain cytosolic
phospholipase A(2), while reducing its net protein level.
Brain Res Bull 2003 Jan 15;59(4):303-6
"Lithium, used to treat bipolar
disorder, has been reported to decrease rat brain mRNA and protein levels of cytosolic
phospholipase A(2) (cPLA(2)), an enzyme that selectively hydrolyzes arachidonic
acid from the stereospecifically numbered (sn)-2 position of membrane phospholipids,
and to decrease PLA(2) activity. cPLA(2) can be activated by being phosphorylated
at its Ser-228, Ser-505, and Ser-727 sites. In this study, we show that the percent
phosphorylated cPLA(2) protein in rat brain is unaffected by lithium. Male Fischer-344
rats were fed lithium chloride for 6 weeks, so as to produce a therapeutically
equivalent brain lithium concentration; control rats were fed lithium-free chow
under parallel conditions. cPLA(2) was immunoprecipitated from brain homogenate
and phosphorylated cPLA(2) protein was quantified using an anti-phosphoserine
antibody, and compared to net cPLA(2) protein. The mean ratio of phosphorylated/total
cPLA(2) was not changed significantly in the lithium-treated compared to the control
group. Thus, decreased brain PLA(2) enzyme activity caused by chronic lithium
is likely a consequence only of lithium's downregulation of cPLA(2) transcription."
[Abstract] Giroux,
Melanie, Descoteaux, Albert
Cyclooxygenase-2 Expression in Macrophages:
Modulation by Protein Kinase C-{alpha}
J Immunol 2000 165:
3985-3991 [Full
Text] Wang, Hui Qin, Kim, Michael P., Tiano, Howard
F., Langenbach, Robert, Smart, Robert C.
Protein Kinase C-{alpha}
Coordinately Regulates Cytosolic Phospholipase A2 Activity and the Expression
of Cyclooxygenase-2 through Different Mechanisms in Mouse Keratinocytes
Mol Pharmacol 2001 59: 860-866 [Full
Text] Subbaramaiah, Kotha, Cole, Philip A., Dannenberg,
Andrew J.
Retinoids and Carnosol Suppress Cyclooxygenase-2 Transcription
by CREB-binding Protein/p300-dependent and -independent Mechanisms
Cancer
Res 2002 62: 2522-2530
"Treatment with retinoic acid (RA) or carnosol,
two structurally unrelated compounds with anticancerproperties, inhibited phorbol
ester (PMA)-mediated induction of activator protein-1 (AP-1) activity and cyclooxygenase-2
(COX-2) expression in human mammary epithelial cells. The induction of COX-2 transcription
by PMA was mediated by increased binding of AP-1 to the cyclic AMP response element
(CRE) of the COX-2 promoter. Inhibition of the histone acetyltransferase activity
of CREB- binding protein (CBP)/p300 blocked the induction of COX-2 by PMA. Treatment
with carnosol but not RA blocked increased binding of AP-1 to the COX-2 promoter.
Because AP-1 binding was unaffected by RA, we investigated whether RA inhibited
COX-2 transcription via effects on the coactivator CBP/p300. Treatment with RA
stimulated an interaction between RA receptor-alpha and CBP/p300; a corresponding
decrease in the interaction between CBP/p300 and c-Jun was observed. Importantly,
overexpressing CBP/p300 or dominant-negative RA receptor-alpha relieved the suppressive
effect of RA on PMA-mediated stimulation of the COX-2 promoter. To elucidate the
mechanism by which carnosol inhibited COX-2 transcription, its effects on protein
kinase C (PKC) signaling were determined. Carnosol but not RA inhibited the activation
of PKC, ERK1/2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinase.
Overexpressing c-Jun but not CBP/p300 reversed the suppressive effect of carnosol
on PMA-mediated stimulation of COX-2 promoter activity. Thus, RA acted by a receptor-dependent
mechanism to limit the amount of CBP/p300 that was available for AP-1-mediated
induction of COX-2. By contrast, carnosol inhibited the induction of COX-2 by
blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2
promoter. Taken together, these results show that small molecules can block the
activation of COX-2 transcription by distinct mechanisms." [Abstract] Qihe
Xu, Tsuneo Konta, Akira Furusu, Kenji Nakayama, Javier Lucio-Cazana, Leon G. Fine,
and Masanori Kitamura
Transcriptional induction of MKP-1 by retinoids:
Selective roles of nuclear receptors and contribution to the anti-apoptotic effect
JBC Papers in Press published on August 16, 2002 as 10.1074/jbc.M207095200
"Among the three RAR subtypes, RARalpha and RARgamma, but not RARbeta, mediated
the t-RA-induced MKP-1 expression. The anti-apoptotic effect of t-RA on H2O2-induced
apoptosis in several cell types was correlated with the inducibility of MKP-1
by t-RA. Inhibition of MKP-1 by vanadate enhanced JNK phosphorylation and attenuated
the anti-apoptotic effect of t-RA. Furthermore, over-expression of MKP-1 inhibited
H2O2-induced JNK phosphorylation and apoptosis." [Abstract/Full
Text]
Schroer K, Zhu Y, Saunders MA, Deng
WG, Xu XM, Meyer-Kirchrath J, Wu KK.
Obligatory role of cyclic adenosine
monophosphate response element in cyclooxygenase-2 promoter induction and feedback
regulation by inflammatory mediators.
Circulation 2002
Jun 11;105(23):2760-5
"CREB-2 and c-Fos binding was increased by phorbol
12-myristate 13-acetate but not tumor necrosis factor-alpha. The binding assay
and chromatin immunoprecipitation revealed binding of P300 coactivator to the
COX-2 promoter region. CONCLUSIONS: CRE plays an obligatory role in COX-2 promoter
activation by diverse stimuli. CREB-2 and ATF-2 bound to CRE serve as an anchor
for P300 interaction with upstream transactivators and downstream transcription
machinery." [Abstract] Zoltán
H. Németh, Edwin A. Deitch, Csaba Szabó, Zoltán Fekete, Carl
J. Hauser, and György Haskó
Lithium Induces NF-kappaB
Activation and Interleukin-8 Production in Human Intestinal Epithelial Cells
J. Biol. Chem. 277: 7713-7719, March 8, 2002.
"Incubation
of human intestinal epithelial cells with lithium induced both enhanced NF-kappaB
DNA binding and NF-kappaB-dependent transcriptional activity. In addition, lithium
stimulated activation of both the p38 and p42/44 MAP kinases." [Abstract] Maria
Torcia, Giovanna De Chiara, Lucia Nencioni, Serena Ammendola, Danilo Labardi,
Maria Lucibello, Paolo Rosini, Lionel N. J. L. Marlier, Paolo Bonini, Persio Dello
Sbarba, Anna Teresa Palamara, Nicola Zambrano, Tommaso Russo, Enrico Garaci, and
Federico Cozzolino
Nerve Growth Factor Inhibits Apoptosis in Memory
B Lymphocytes via Inactivation of p38 MAPK, Prevention of Bcl-2 Phosphorylation,
and Cytochrome c Release
J. Biol. Chem. 276: 39027-39036,
October 2001. [Full
Text]
Hedgepeth CM, Conrad LJ, Zhang J, Huang
HC, Lee VM, Klein PS.
Activation of the Wnt signaling pathway: a
molecular mechanism for lithium action.
Dev Biol 1997 May
1;185(1):82-91
"Using a novel assay for GSK-3 beta in oocytes, we show
that lithium inhibits GSK-3 beta from species as diverse as Dictyostelium discoideum
and Xenopus laevis, providing a biochemical mechanism for the action of lithium
on the development of these organisms. Lithium treatment also leads to activation
of an AP-1-luciferase reporter in Xenopus embryos, consistent with previous observations
that GSK-3 beta inhibits c-jun activity. Activation of the wnt pathway with a
dominant negative form of GSK-3 beta is inhibited by myo-inositol, similar to
the previously described effect of coinjecting myo-inositol with lithium. The
mechanism by which myo-inositol inhibits both dominant negative GSK-3 beta and
lithium remains uncertain." [Abstract]
Ren-Wu Chen, and De-Maw Chuang
Long
Term Lithium Treatment Suppresses p53 and Bax Expression but Increases Bcl-2 Expression.
A PROMINENT ROLE IN NEUROPROTECTION AGAINST EXCITOTOXICITY
J. Biol. Chem. 274: 6039-6042, March 1999. [Full
Text]
Scotto, Christian, Delphin, Christian,
Deloulme, Jean Christophe, Baudier, Jacques
Concerted Regulation
of Wild-Type p53 Nuclear Accumulation and Activation by S100B and Calcium-Dependent
Protein Kinase C
Mol. Cell. Biol. 1999 19: 7168-7180 [Full
Text] Mora, Alfonso, Sabio, Guadalupe, Gonzalez-Polo,
Rosa A., Cuenda, Ana, Alessi, Dario R., Alonso, Juan C., Fuentes, Jose M., Soler,
German, Centeno, Francisco
Lithium inhibits caspase 3 activation
and dephosphorylation of PKB and GSK3 induced by K+ deprivation in cerebellar
granule cells
J Neurochem 2001 78: 199-206
"As
lithium did not inhibit caspase 3 activity in vitro, these results suggest that
this ion inhibits an upstream component that is required for caspase 3 activation."
[Abstract]
King TD, Bijur GN, Jope RS.
Caspase-3 activation
induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase
kinase-3beta and attenuated by lithium.
Brain Res 2001
Nov 16;919(1):106-14 [Abstract] Ghribi
O, Herman MM, Spaulding NK, Savory J.
Lithium inhibits aluminum-induced
apoptosis in rabbit hippocampus, by preventing cytochrome c translocation, Bcl-2
decrease, Bax elevation and caspase-3 activation.
J Neurochem
2002 Jul;82(1):137-45 [Abstract]
Wang HY, Friedman E.
Lithium inhibition
of protein kinase C activation-induced serotonin release.
Psychopharmacology
(Berl) 1989;99(2):213-8
"In parietal cortical slices, PMA elicited increase
in K+-evoked [3H]NE release was prevented in slices taken from lithium-treated
(3 weeks) animals. Lithium treatment did not affect the activity and distribution
of protein kinase C in cortical tissue. However, 3 weeks of treatment reduced
the PMA-induced translocation of the enzyme. These results suggest that lithium
treatment interferes with serotonin and norepinephrine release facilitation which
results from the stimulation of PKC by phorbol esters. These actions of the ion
may be mediated by its ability to inhibit PMA induced PKC translocation."
[Abstract] Shaldubina
A, Agam G, Belmaker RH.
The mechanism of lithium action: state of
the art, ten years later.
Prog Neuropsychopharmacol Biol
Psychiatry 2001 May;25(4):855-66
"Inhibition of 5HT autoreceptors by
lithium is supported by biochemical and behavioral data in rats but would seem
more related to lithium's antidepressant than to its antimanic or prophylactic
effects. Lithium induces increases in levels of the anti-apoptotic factor Bcl-2.
This effect could be most relevant for treatment of neurodegenerative disorders.
Lithium inhibits glycogen synthase kinase-3, which is involved in a wide range
of signal transduction pathways. However, this lithium effect occurs at high concentrations
and may be more relevant for its toxic effect." [Abstract] Chen,
G, Yuan, PX, Jiang, YM, Huang, LD, Manji, HK
Lithium increases tyrosine
hydroxylase levels both in vivo and in vitro
J Neurochem
1998 70: 1768-1771 [Abstract]
Kumer,
SC, Vrana, KE
Intricate regulation of tyrosine hydroxylase activity
and gene expression
J Neurochem 1996 67: 443-462 [Abstract]
Kim SJ, Im DS, Kim SH, Ryu JH, Hwang SG,
Seong JK, Chun CH, Chun JS.
Beta-catenin regulates expression of
cyclooxygenase-2 in articular chondrocytes.
Biochem Biophys
Res Commun 2002 Aug 9;296(1):221-6
"Inhibition of beta-catenin degradation
by the treatment of cells with LiCl or proteasome inhibitor stimulated expression
of COX-2, indicating that transcriptionally active beta-catenin is sufficient
to induce COX-2 expression. This was demonstrated further by the observation that
ectopic expression of transcriptionally competent beta-catenin stimulated expression
of COX-2." [Abstract] Li,
X, Jope, RS
Selective inhibition of the expression of signal transduction
proteins by lithium in nerve growth factor-differentiated PC12 cells
J
Neurochem 1995 65: 2500-2508
"This investigation examined if lithium,
the primary therapeutic treatment for bipolar affective disorder, modulated the
levels of selected signal transduction proteins in PC12 cells. Nerve growth factor
(NGF) induced differentiation of PC12 cells, and after 12 days of NGF treatment
there were large increases in the levels of the heterotrimeric G protein subunits
alpha o1, alpha i1, beta, and alpha s, small increases in those of alpha i2 and
alpha q, and a slight decrease in that of alpha o2. Lithium (1 mM, equivalent
to the therapeutic concentration) selectively reduced NGF-induced increases in
levels of G protein subunits, generally having the greatest inhibition on those
that were increased the most by NGF. Lithium at 5 mM had greater inhibitory effects
than 1 mM lithium on NGF-induced increases in levels of G proteins, but neither
concentration of lithium affected the induction of the cytoskeletal protein beta-tubulin.
Examination of other proteins involved in signal transduction revealed that 12
days of NGF treatment increased the level of protein kinase C-alpha, but not those
of the beta, epsilon, or zeta subtypes, and did not alter the levels of beta,
gamma, or delta phospholipase C. Pretreatment with lithium inhibited the increase
in content of protein kinase C-alpha induced by NGF but had little effect on the
proteins not responsive to NGF except for decreasing the levels of protein kinase
C-epsilon. The inhibitory effect of lithium was found not to be due to inhibition
of NGF-induced tyrosine phosphorylation, which was unaffected by 5 mM lithium,
or to inositol depletion. In summary, use of the dynamic system of NGF-induced
PC12 cell differentiation provided a sensitive model in which to identify signal
transduction proteins that were influenced by lithium treatment. The large changes
caused by a therapeutically equivalent concentration of lithium lend support to
the proposal that the selective inhibitory effects of lithium on subtypes of G
proteins and protein kinase C may be important therapeutic targets." [Abstract]
Peter
Schotte, Geert Van Loo, Isabelle Carpentier, Peter Vandenabeele, and Rudi Beyaert
Lithium Sensitizes Tumor Cells in an NF-kappaB-independent Way
to Caspase Activation and Apoptosis Induced by Tumor Necrosis Factor (TNF). EVIDENCE
FOR A ROLE OF THE TNF RECEPTOR-ASSOCIATED DEATH DOMAIN PROTEIN
J. Biol. Chem. 276: 25939-25945, July 2001.
"So far, the underlying mechanism
for TNF/lithium synergism is still unclear." [Full
Text]
Natalie J. Avdi, Malcolm, Kenneth C,
Nick, Jerry A, and G. Scott Worthen
p38 mitogen-activated protein
kinase-mediated regulation of the c-Jun NH2 terminal kinase pathway in human neutrophils:
A role for PP2A
JBC Papers in Press published on August
16, 2002 as 10.1074/jbc.M204455200
"The studies
described here demonstrate functional crosstalk between the p38 and JNK pathways
in TNF alpha-stimulated neutrophils, whereby p38 MAPk acts to limit the activation
of JNK by PP2A-mediated inhibition of MKK4 (Fig. 10)." [Abstract/Full
Text] Zhen X, Torres C, Friedman E.
Lithium regulates protein tyrosine phosphatase activity in vitro and in vivo.
Psychopharmacology (Berl) 2002 Aug;162(4):379-84
"Lithium
stimulated protein tyrosine phosphatase (PTPase) activity in a dose- and time-dependent
manner in PC12 cells. A maximal stimulation of 87% was observed after 6 h of incubation
with 3 mM LiCl. In contrast, protein serine phosphatase (PSPase) activity was
not changed by lithium. The stimulatory effect on PTPase was not due to a direct
action of the ion on the enzymes, but its selectivity was noted since treatment
of cells with other monovalent cations exhibited no effect on PTPase activity.
Lithium appeared to target specific PTPase(s) as it stimulated membrane-associated
PTPase activity without affecting cytosolic or nuclear enzymatic activities. Moreover,
the stimulation of PTPase activity in PC12 cells by lithium is independent of
de novo protein synthesis. In the rat, 3 weeks of lithium treatment significantly
elevated PTPase activity in hippocampus, striatum and cortex." [Abstract]
Moorman JM, Leslie RA.
Paradoxical effects
of lithium on serotonergic receptor function: an immunocytochemical, behavioural
and autoradiographic study.
Neuropharmacology 1998;37(3):357-74
"Treatment of rats with chronic lithium significantly enhanced DOI-induced
locomotor activity and Fos-like immunoreactivity throughout the cerebral cortex.
This elevation in Fos-like immunoreactivity was completely abolished by prior
treatment with ritanserin. In contrast, chronic lithium treatment had no effect
on the density of [3H]ketanserin binding to 5-HT2A receptors in any brain region
examined. The results of the time-course experiment demonstrated that the enhancing
effect of lithium on 5-HT2A/2C receptor-mediated Fos expression was short-lived
such that Fos-like immunoreactivity returned to untreated levels within 48 h.
In the acute lithium experiment, administration of lithium to rats 12 or 24 h
before DOI resulted in a similar elevation of Fos-like immunoreactivity to that
seen in chronically treated animals. Administration of acute lithium 36 or 48
h before DOI had no effect. The effects of lithium on 5-HT2A/2C receptor function
thus appear to be complex. In particular, the results of this study indicate that
the enhancing effects of lithium on DOI-induced locomotor activity and Fos-like
immunoreactivity are not accompanied by any alteration in the density of 5-HT2A
receptor binding sites. If changes in receptor numbers therefore do not account
for the physiological effect of chronic lithium, other explanations must be sought.
The study also suggests that the inositol depletion hypothesis of lithium's therapeutic
action does not adequately explain the mechanism of action of lithium in man."
[Abstract]
Lopez-Coronado JM, Belles JM, Lesage F, Serrano R, Rodriguez
PL.
A novel mammalian lithium-sensitive enzyme with a dual enzymatic
activity, 3'-phosphoadenosine 5'-phosphate phosphatase and inositol-polyphosphate
1-phosphatase.
J Biol Chem 1999 Jun 4;274(23):16034-9
"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." [Full
Text] Patel S, Yenush L, Rodriguez PL, Serrano
R, Blundell TL.
Crystal structure of an enzyme displaying both inositol-polyphosphate-1-phosphatase
and 3'-phosphoadenosine-5'-phosphate phosphatase activities: a novel target of
lithium therapy.
J Mol Biol. 2002 Jan 25;315(4):677-85.
"Lithium
cations exert profound and selective psychopharmacological effects on ameliorate
manic-depressive psychosis. Although lithium is an effective drug for both treatment
and prophylaxis of bipolar disorder, the precise mechanism of action is not well
understood. Lithium acts as both an uncompetitive and non-competitive inhibitor
of several lithium- sensitive phosphatases with regard to substrate and magnesium
cofactor, respectively. In this work, we report the crystal structure and reaction
mechanism of Rattus norvegicus 3'-phosphoadenosine 5'-phosphate and inositol 1,4-bisphosphate
phosphatase (RnPIP), a recently identified target of lithium therapy. This Li(+)-sensitive
enzyme plays a crucial role in several cellular processes, such as RNA processing,
sulphation reactions and probably inositol recycling. RnPIP specifically removes
the 3'-phosphate group of 3'-phosphoadenosine 5'-phosphate (PAP) and the 1'-phosphate
group of inositol 1,4-bisphosphate (I(1),(4)P(2)) producing AMP and inositol 4'-phosphate,
respectively. The crystal structure of RnPIP complexed with AMP, Pi and magnesium
ions at 1.69 A resolution provides insight into the reaction mechanism of the
hydrolysis of PAP. The core fold of the enzyme is equivalent to that found in
other Li(+)-sensitive phosphatases, such as inositol monophosphatase, but molecular
modelling of I(1),(4)P(2) in the RnPIP active site reveals important structural
determinants that accommodate this additional substrate. RnPIP is potently inhibited
by lithium and, as the accumulation of PAP inhibits a variety of proteins, including
sulphotransferases and RNA processing enzymes, this dual specificity enzyme represents
a potential target of lithium action, in addition to inositol monophosphatases."
[Abstract] Agam
G, Shaltiel G.
Possible role of 3'(2')-phosphoadenosine-5'-phosphate
phosphatase in the etiology and therapy of bipolar disorder.
Prog
Neuropsychopharmacol Biol Psychiatry. 2003 Aug;27(5):723-7.
"Bipolar affective
disorder (BPD) is a multifactorial, severe, chronic and disabling illness with
50% heritability that affects 1-2% of the population. Lithium ions (Li) are the
drug of choice for BPD. Yet, 20-40% of patients fail to respond to Li. Although
numerous biochemical and cellular effects have been attributed to Li, its therapeutic
mechanism of action has not been elucidated. This review presents the possible
involvement of 3'(2')-phosphoadenosine-5'-phosphate (PAP) phosphatase in the etiology
of bipolar disorder and the mechanism of action of Li. Of the enzymes inhibited
by Li, PAP phosphatase is inhibited with the lowest Ki (0.3 mM). At therapeutic
concentrations of Li (0.5-1.5 mM), inhibition is greater than 80%. Therefore,
PAP phosphatase is a strong candidate for Li's therapeutic mechanism of action.
In yeast, a PAP phosphatase knockout mutation leads to the accumulation of PAP,
which affects ribosomal-, transfer- and small nucleolar-RNA processing. PAP accumulation
in the mammalian brain following Li inhibition of PAP phosphatase may very well
account for the observed effects of Li on gene expression and behavior. Furthermore,
we have reported significant changes in PAP phosphatase levels in postmortem frontal
cortex of bipolar patients." [Abstract] Agam
G, Shatiel G, Kozlovsky N, Shimon H, Belmaker RH.
Lithium inhibitable
enzymes in postmortem brain of bipolar patients.
J Psychiatr
Res. 2003 Sep-Oct;37(5):433-42.
"Despite considerable ongoing efforts
at the epidemiological, genetic and molecular level, the etiology of bipolar disorder
had not yet been elucidated. To study possible contributing components to the
pathophysiology of this disorder, we have hypothesized that levels of enzymes
inhibited by therapeutically relevant lithium ion concentrations in the brain
of patients may differ from those in normal controls and may be involved in the
etiology of the disorder. Three Li-inhibitable enzymes were studied in postmortem
brain samples of bipolar patients and normal controls. The expression and function
of the two enzymes that are obviously involved in signaling cascades, IMPase,
involved in the second messenger system of the phosphatidylinositol cycle, and
GSK-3, a mediator of an array of signaling cascades, were not found to be different
in postmortem frontal and occipital cortex of bipolar patients and normal controls.
Only PAP phosphatase protein levels, but not its mRNA levels or enzymatic activity,
were found to be significantly decreased in frontal cortex of bipolar patients
compared with normal controls." [Abstract] Gould
TD, Chen G, Manji HK.
In Vivo Evidence in the Brain for Lithium Inhibition
of Glycogen Synthase Kinase-3.
Neuropsychopharmacology.
2003 Aug 27 [Epub ahead of print].
"There is considerable interest in
the possibility that small-molecule glycogen synthase kinase-3 inhibitors may
have utility in the treatment of bipolar disorder, since glycogen synthase kinase-3
is a target of lithium. Although the in vitro inhibition of glycogen synthase
kinase-3 by lithium occurs with a K(i) of 1-2 mM, the degree of inhibition of
this enzyme in the mammalian brain at therapeutically relevant concentrations
has not fully been established. The transcription factor beta-catenin is an established
marker of glycogen synthase kinase-3 inactivation because cytoplasmic levels are
increased by inhibition of the enzyme. In this study, we measured beta-catenin
protein levels after treatment with therapeutically relevant doses of lithium,
valproate, and carbamazepine. Western blot revealed that 9 days of treatment with
lithium and valproate, but not carbamazepine, increased beta-catenin protein levels
in soluble fractions from the frontal cortex. The level of beta-catenin in the
particulate fraction, which is not directly regulated by glycogen synthase kinase-3,
did not change with any of the three drugs. Furthermore, real-time PCR revealed
that lithium significantly decreased beta-catenin mRNA levels, which may represent
compensation for an increase in beta-catenin stability. These results strongly
suggest that lithium significantly inhibits brain glycogen synthase kinase-3 in
vivo at concentrations relevant for the treatment of bipolar disorder." [Abstract] Vreugdenhil
M, Wadman WJ.
Modulation of sodium currents in rat CA1 neurons by
carbamazepine and valproate after kindling epileptogenesis.
Epilepsia
1999 Nov;40(11):1512-22
"PURPOSE: To determine the modulation of sodium
currents in hippocampal CA1 neurons by carbamazepine (CBZ) and valproate (VPA),
before and after kindling epileptogenesis. METHODS: Voltage-dependent sodium current
was measured in isolated hippocampal CA1 neurons, by using the whole-cell voltage-clamp
technique. CBZ (15-100 microM) or VPA (0.5-5 mM) was applied by bath perfusion.
Cells from fully kindled rats were compared with controls, 1 day and 5 weeks after
the tenth generalized seizure. RESULTS: CBZ did not affect sodium current activation
but selectively shifted the voltage dependence of steady-state inactivation to
more hyperpolarized potentials. One day after the last kindled generalized seizure,
the shift induced by 15 microM CBZ was 2.1+/-0.5 mV (mean +/- SEM; n = 20) compared
with 4.3+/-0.3 mV (n = 16; p<0.001) in matched controls. The EC50 of the concentration-effect
relation was 57+/-6 microM compared with 34+/-2 microM (p<0.01) in controls.
Five weeks after kindling, these values had recovered to a level not different
from control. VPA induces at a relatively high concentration a similar but smaller
shift in voltage dependence of inactivation than does CBZ. After kindling, the
shift induced by 2 mM VPA (2.8+/-0.6 mV; n = 19) was not different from controls
(3.0+/-0.5 mV; n = 22). The EC50 for VPA was 2.6+/-0.3 mM compared with 2.5+/-0.4
mM in controls. CONCLUSIONS: Both CBZ and VPA selectively modulate the voltage
dependence of sodium current steady-state inactivation and as a consequence reduce
cellular excitability. The effect of CBZ was reduced immediately after kindling
epileptogenesis, apparently by a reduced affinity of its receptor. In contrast,
the shift induced by VPA was not different at any stage after kindling epileptogenesis.
The change in CBZ sensitivity after kindling is related to epileptic activity
rather than to the epileptic state, because it almost completely recovers in a
period without seizures." [Abstract]
Yatham, Lakshmi N., Liddle, Peter F., Lam, Raymond
W., Shiah, I-Shin, Lane, Carol, Stoessl, A. Jon, Sossi, Vesna, Ruth, Thomas J.
PET Study of the Effects of Valproate on Dopamine D2 Receptors in Neuroleptic-
and Mood-Stabilizer-Naive Patients With Nonpsychotic Mania
Am J Psychiatry 2002 159: 1718-1723
"OBJECTIVE: A previous study reported
a higher than normal density of dopamine D2 receptors in psychotic mania but not
in nonpsychotic mania. The purpose of this study was to further examine D2 receptor
density in a larger sample of nonpsychotic manic patients by using positron emission
tomography (PET) and [11C]raclopride. METHOD: Thirteen neuroleptic- and mood-
stabilizer-naive patients with DSM-IV mania without psychotic features and 14
healthy comparison subjects underwent [11C]raclopride PET scans. Of the 13 patients,
10 were treated with divalproex sodium monotherapy. PET scans were repeated 2–6
weeks after commencement of divalproex sodium. D2 receptor binding potential was
calculated by using a ratio method with the cerebellum as the reference region.
RESULTS: The [11C]raclopride D2 binding potential was not significantly different
in manic patients than in the comparison subjects in the striatum. Treatment with
divalproex sodium had no significant effect on the [11C]raclopride D2 binding
potential in manic patients. There was no correlation between the D2 binding potential
and manic symptoms before or after treatment. CONCLUSIONS: These results suggest
that D2 receptor density is not altered in nonpsychotic mania and that divalproex
sodium treatment does not affect D2 receptor availability." [Abstract] |
V Asghari, JF Wang, JS Reiach, and LT Young
Differential effects of mood stabilizers on Fos/Jun proteins and
AP-1 DNA binding activity in human neuroblastoma SH-SY5Y cells.
Brain
Res Mol Brain Res, Jul 1998; 58(1-2): 95-102.
"At therapeutically relevant
concentrations, both drugs acutely (<24 h) induced c-Fos immunoreactivity and
AP-1 binding. In contrast to lithium, chronic (1 week) treatment with VPA led
to continued induction of c-Fos, in addition to induction of c-Jun immunoreactivity
and a 33-35 kDa band previously identified as chronic FRA. AP-1 DNA binding activity
was also increased after 1 week VPA treatment. These findings suggest that both
these mood stabilizers may have an effect on neuronal gene expression of target
genes containing the AP-1 consensus sequence in their promoter regions after acute
treatment." [Abstract] Jin
C, Li H, Murata T, Sun K, Horikoshi M, Chiu R, Yokoyama KK.
JDP2,
a repressor of AP-1, recruits a histone deacetylase 3 complex to inhibit the retinoic
acid-induced differentiation of F9 cells.
Mol Cell Biol
2002 Jul;22(13):4815-26
"Up-regulation of the c-jun gene is a critical
event in the retinoic acid (RA)-mediated differentiation of embryonal carcinoma
F9 cells. Activating transcription factor 2 (ATF-2) and p300 cooperate in the
activation of transcription of the c-jun gene during the differentiation of F9
cells. We show here that the overexpression of Jun dimerization protein 2 (JDP2),
a repressor of AP-1, inhibits the transactivation of the c-jun gene by ATF-2 and
p300 by recruitment of the histone deacetylase 3 (HDAC3) complex, thereby repressing
the RA-induced transcription of the c-jun gene and inhibiting the RA-mediated
differentiation of F9 cells. Moreover, chromatin immunoprecipitation assays showed
that the JDP2/HDAC3 complex, which binds to the differentiation response element
within the c-jun promoter in undifferentiated F9 cells, was replaced by the p300
complex in response to RA, with an accompanying change in the histone acetylation
status of the chromatin, the initiation of transcription of the c-jun gene, and
the subsequent differentiation of F9 cells. These results suggest that JDP2 may
be a key factor that controls the commitment of F9 cells to differentiation and
shed new light on the mechanism by which an AP-1 repressor functions." [Abstract]
Christopher J. Phiel, Fang Zhang, Eric Y. Huang, Matthew
G. Guenther, Mitchell A. Lazar, and Peter S. Klein
Histone Deacetylase
Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer,
and Teratogen
J. Biol. Chem. 276: 36734-36741, September
2001.
"At therapeutic levels, valproic acid mimics the histone deacetylase
inhibitor trichostatin A, causing hyperacetylation of histones in cultured cells.
Valproic acid, like trichostatin A, also activates transcription from diverse
exogenous and endogenous promoters. Furthermore, valproic acid and trichostatin
A have remarkably similar teratogenic effects in vertebrate embryos, while non-teratogenic
analogues of valproic acid do not inhibit histone deacetylase and do not activate
transcription." [Full
Text] Rickard KL, Gibson PR, Wilson NJ, Mariadason
JM, Phillips WA.
Short-chain fatty acids reduce expression of specific
protein kinase C isoforms in human colonic epithelial cells.
J
Cell Physiol 2000 Feb;182(2):222-31
"LIM1215 colon cancer cells were used
as a model of human colonic epithelium to examine the effects of butyrate on protein
kinase C (PKC) activity and isoform expression. On Western blot analysis, LIM1215
cells express the PKC isoforms alpha, beta, varepsilon, zeta, and lambda, but
not gamma, straight theta, or micro. Treatment with 2 mM butyrate for 48 h reduced
cellular PKC activity up to 50% and specifically reduced the expression of PKCalpha
and PKCvarepsilon. Similar results were obtained using Caco-2 colon cancer cells.
These effects were neither a consequence of the induction of differentiation itself
nor the result of direct or indirect activation of PKC. Although dependent on
gene transcription and protein synthesis, the effect was not due to a reduction
in the synthesis of PKC protein. Butyrate's effect was independent of its beta-oxidation
but was mimicked, at least in part, by trichostatin A, an inhibitor of histone
deacetylase." [Abstract]
Chung, Yih-Lin, Lee, Yan-Hwa Wu, Yen, Sang-Hue, Chi,
Kwan-Hwa
A Novel Approach for Nasopharyngeal Carcinoma Treatment
Uses Phenylbutyrate as a Protein Kinase C Modulator: Implications for Radiosensitization
and EBV-targeted Therapy
Clin Cancer Res 2000 6: 1452-1458
"Sodium
phenylbutyrate (NaPB) represent a new non-toxic class of compounds with antiproliferative
activities to different tumors and has been shown to modulate many gene expressions
by inhibiting histone deacetylation and DNA methylation as the major mechanism.
Butyrate and other protein kinase C (PKC) activators have been reported to be
able to activate virus enzymes. The present work investigates whether NaPB has
an antiproliferative effect or modulatory effects on EBV-associated nasopharyngeal
carcinoma (NPC) and whether EBV thymidine kinase gene can be activated to make
cells susceptible to ganciclovir (GCV) therapy. NaPB treatme |
