[For more information on the relationship between mood stabilizers and protein
kinase C (PKC), please click here.]
CG, Friedman E.
Abnormalities in protein kinase C signaling and the
pathophysiology of bipolar disorder.
Bipolar Disord 1999
"Protein kinase C (PKC) is a group of calcium and phospholipid-dependent
enzymes, which plays a pivotal role in cell signaling systems. Recently accumulated
evidence indicates that alterations in PKC activity play a significant role in
the pathophysiology of bipolar disorder. A number of laboratories investigated
the effect of mood stabilizers on the regulation of PKC activity in bipolar patients,
in animals, and in cultured cells. Following chronic lithium treatment, PKC activation
was significantly reduced in rat brains, as measured by the translocation of cytoplasmic
PKC to the membrane compartment, or by quantitative binding of the PKC ligand,
PDBu. The effect of the therapeutic concentration of lithium in attenuating PKC-dependent
intracellular parameters was also demonstrated in cultured cells. More importantly,
alterations in platelet PKC was shown in bipolar patients during the manic state
of the illness. In comparison to patients with major depressive disorder, schizophrenia,
or healthy controls, PKC activity was significantly increased in manic patients,
suggesting that changes in PKC may be an illness-specific marker. Interestingly,
enhanced PKC activity during mania was suppressed following mood-stabilizer treatment
as manic symptoms improved. In parallel to the findings in platelets, postmortem
studies demonstrate that membrane-associated PKC and stimulation-induced translocation
of cytosolic enzyme to the membrane were also increased in frontal cortex of bipolar
patients. Other studies suggest alterations in other signal transduction mechanisms
in bipolar disorder. These include alterations in G protein activation, phosphatidylinositol
(PI) signaling, cyclic AMP formation, and intracellular calcium homeostasis. The
alterations of PKC activity in bipolar disorder may be related to changes in these
other intracellular signaling mechanisms. Alternatively, the changes of PKC activity
may be the core pathology of the illness. More studies are required to further
characterize the association of PKC changes with bipolar disorder, using a proper
neuronal model." [Abstract]
HY, Friedman E.
Enhanced protein kinase C activity and translocation
in bipolar affective disorder brains.
Biol Psychiatry 1996
"Protein kinase C (PKC) activity and its redistribution
were determined in the frontal cortices of postmortem brains of bipolar affective
disorder subjects and age-, sex-, and postmortem time-matched controls. Membrane
and cytosolic PKC activity was determined by histone phosphorylation using [32P]-adenosine
triphosphate as substrate. Specific PKC isozyme levels were assessed by Western
blot analysis using antipeptide antibodies. Brain membrane-associated PKC activity
was higher in bipolar vs. control tissue. An examination of the specific PKC isozymes
in cortical homogenates revealed that cytosolic alpha- and membrane-associated
gamma- and zeta PKC isozymes were elevated in cortices of bipolar affective disorder
subjects, whereas cytosolic epsilon PKC was found to be reduced. In control brain
slices, incubation with 1 mumol/L phorbol 12-myristate 13-acetate (PMA) caused
an increase in membrane PKC activity, whereas cytosolic enzyme activity was decreased.
This redistribution of the enzyme by PMA was markedly potentiated in brain slices
of bipolar subjects. The results suggest that PKC-mediated phosphorylation is
increased in brains of subjects with bipolar affective illness." [Abstract]
H, Friedman E.
Increased association of brain protein kinase C with
the receptor for activated C kinase-1 (RACK1) in bipolar affective disorder.
Psychiatry 2001 Sep 1;50(5):364-70
"BACKGROUND: Membrane protein kinase
C (PKC) activity is increased in frontal cortex of subjects with bipolar affective
disorder, and lithium was demonstrated to inhibit PKC translocation to membranes.
Protein kinase C is anchored to the membrane via the receptor for activated C
kinase-1 (RACK1), suggesting that interactions between these proteins may be altered
in bipolar disease. METHODS: The levels of RACK1 coimmunoprecipitating with PKC
isozymes were compared in homogenates of frontal cortex slices from postmortem
bipolar subjects and matched control subjects. RESULTS: Receptor for activated
C kinase-1 was located exclusively in membranes and, in control brains, the levels
of RACK1 that coimmunoprecipitated with most PKC isozymes were increased by stimulation
with the PKC activator, phorbol 12-myristate, 13-acetate (PMA). The association
of RACK1 with membrane gammaPKC and zetaPKC was increased under basal conditions
in bipolar relative to control brains. Stimulation with PMA increased the amount
of RACK1 that coimmunoprecipitated with the alpha, beta, gamma, delta, and varepsilonPKC
isozymes, but not zetaPKC, in bipolar tissues over that elicited in control tissues.
CONCLUSIONS: These data suggest that the increased association of RACK1 with PKC
isozymes may be responsible for the increases in membrane PKC and in its activation
that were previously observed in frontal cortex of bipolar affective disorder
PV, Garcia-Sevilla JA.
Parallel modulation of receptor for activated
C kinase 1 and protein kinase C-alpha and beta isoforms in brains of morphine-treated
Br J Pharmacol 1999 May;127(2):343-8
for activated C kinase 1 (RACK1) is an intracellular receptor for protein kinase
C (PKC) that regulates the cellular enzyme localization. Because opiate drugs
modulate the levels of brain PKC (Ventayol et al., 1997), the aim of this study
was to assess in parallel the effects of morphine on RACK1 and PKC-alpha and beta
isozymes densities in rat brain frontal cortex by immunoblot assays. 2. Acute
morphine (30 mg kg(-1), i.p., 2 h) induced significant increases in the densities
of RACK1 (33%), PKC-alpha (35%) and PKC-beta (23%). In contrast, chronic morphine
(10-100 mg kg(-1), i.p., 5 days) induced a decrease in RACK1 levels (22%), paralleled
by decreases in the levels of PKC-alpha (16%) and PKC-beta (16%). 3. Spontaneous
(48 h) and naloxone (2 mg kg(-1), i.p., 2 h)-precipitated morphine withdrawal
after chronic morphine induced marked up-regulations in the levels of RACK1 (38-41%),
PKC-alpha (51-52%) and PKC-beta (48-62%). 4. In the same brains and for all combined
treatments, there were significant positive correlations between the density of
RACK1 and those of PKC-alpha (r=0.85, n = 35) and PKC-beta (r=0.75, n=32). 5.
These data indicate that RACK1 is involved in the short- and long-term effects
of morphine and in opiate withdrawal, and that RACK1 modulation by morphine or
its withdrawal is parallel to those of PKC-alpha and beta isozymes. Since RACK1
facilitates the PKC substrate accessibility, driving its cellular localization,
the coordinate regulation of the PKC/RACK system by morphine could be a relevant
molecular mechanism in opiate addiction." [Abstract]
MP, Freed WJ, Kleinman JE.
Neuropathology of bipolar disorder.
Psychiatry 2000 Sep 15;48(6):486-504
"The literature on the neuropathology
of bipolar disorder (BD) is reviewed. Postmortem findings in the areas of pathomorphology,
signal transduction, neuropeptides, neurotransmitters, cell adhesion molecules,
and synaptic proteins are considered. Decreased glial numbers and density in both
BD and major depressive disorder (MDD) have been reported, whereas cortical neuron
counts were not different in BD (in Brodmann's areas [BAs] 9 and 24). In contrast,
MDD patients showed reductions in neuronal size and density (BA 9, BA 47). There
are a number of findings of alterations in neuropeptides and monoamines in BD
brains. Norepinephrine turnover was increased in several cortical regions and
thalamus, whereas the serotonin metabolite, 5-hydroxyindoleacetic acid, and the
serotonin transporter were reduced in the cortex. Several reports further implicated
both cyclic adenosine monophosphate and phosphatidylinositol (PI) cascade abnormalities.
G protein concentrations and activity increases were found in the occipital, prefrontal,
and temporal cortices in BD. In the PI signal cascade, alterations in PKC activity
were found in the prefrontal cortex. In the occipital cortex, PI hydrolysis was
decreased. Two isoforms of the neural cell adhesion molecules were increased in
the hippocampus of BD, whereas the synaptic protein marker, synaptophysin, was
not changed. The findings of glial reduction, excess signal activity, neuropeptide
abnormalities, and monoamine alterations suggest distinct imbalances in neurochemical
regulation. Possible alterations in pathways involving ascending projections from
the brain stem are considered. Larger numbers of BD brains are needed to further
refine the conceptual models that have been proposed, and to develop coherent
models of the pathophysiology of BD." [Abstract]
K, Kusumi I, Akimoto T, Sasaki Y, Koyama T.
Calcium Response in the Presence of Staurosporine in Blood Platelets from Bipolar
Neuropsychopharmacology. 2003 Jun;28(6):1210-4.
have reported that the platelet intracellular calcium (Ca) mobilization after
stimulation by serotonin (5-HT) is specifically enhanced in bipolar disorder among
various psychiatric disorders, compared with that in normal control. To explore
the mechanisms of enhanced Ca response to 5-HT in the platelets, we first examined
the relation between the 5HT-elicited Ca mobilization and 5-HT(2A) receptor density
using the platelets from 13 normal subjects. From this study, we found no significant
correlation between two measures. Then, we investigated the effects of staurosporine,
a protein kinase C (PKC) inhibitor, on Ca response to 5-HT in platelets from patients
with major depressive disorder (unipolar), bipolar disorder, and normal controls.
While 5-HT-induced Ca mobilization, in the presence of 100 nM staurosporine, was
significantly attenuated in normal controls and patients with major depressive
disorder, the inhibitory effect of staurosporine was not observed in bipolar disorder.
These results suggest that the failure in inhibiting the platelet intracellular
Ca response to 5-HT in bipolar disorder may be related to increased activity of
PKC rather than increased 5-HT(2A) receptor number. Moreover, the trend of the
Ca response towards staurosporine may become a specific biological marker for
unipolar-bipolar dichotomy." [Abstract] [Full Text]
E, Hoau-Yan-Wang, Levinson D, Connell TA, Singh H.
protein kinase C activity in bipolar affective disorder, manic episode.
Psychiatry 1993 Apr 1;33(7):520-5 [Abstract]
HY, Markowitz P, Levinson D, Undie AS, Friedman E.
protein kinase C activity and translocation in blood platelets from bipolar affective
J Psychiatr Res 1999 Mar-Apr;33(2):171-9
recent investigations have suggested that the phosphoinositide (PI) signal transduction
system may be involved in the pathophysiology of bipolar affective disorders.
Earlier studies in our laboratory have implicated altered PKC-mediated phosphorylation
in bipolar affective disorder and in the clinical action of lithium. In the present
study, we compared PKC activity and its translocation in platelets from subjects
with bipolar affective disorder and three other groups. METHODS: subjects included
44 with bipolar disorder (acute manic episode), 25 with acute major depression,
23 with schizophrenia in acute exacerbation and 43 controls free of personal or
family history of an Axis I disorder. Blood platelet membrane and cytosol PKC
activity was measured before and after in vitro stimulation with serotonin (5-HT),
thrombin and the direct PKC activator, PMA. In addition, we examined 5-HT-, thrombin-
and PMA-elicited translocations of PKC isozymes from cytosol to the membrane in
platelets of control subjects. RESULTS: in the basal state, manic subjects demonstrated
higher membrane PKC activity than depressive and control subjects. The ratio of
membrane to cytosol PKC activity was significantly higher in manic (1.10), as
compared to control (0.84), depressed (0.93) or schizophrenic (0.93) subjects.
Stimulation of platelets with 5-HT in vitro, resulted in greater membrane to cytosol
ratio in the manic subjects compared to the three other groups. The responsiveness
of platelets to PMA and thrombin was greater for manic subjects than for depressed
and schizophrenic subjects, but not greater than the controls. In this measure
both the schizophrenic and depressive groups were less active than controls. The
results also demonstrate that platelets contain alpha-, beta-, delta- and zeta-PKC
isozymes. While alpha- and beta-PKC isoforms were translocated from cytosol to
membrane in response to serotonin, PMA and thrombin, serotonin also elicited the
redistribution of delta-PKC and thrombin also activated zeta-PKC. CONCLUSION:
the results demonstrate that a heightened PKC-mediated signal transduction is
associated with acute mania and suggest a decreased transduction in patients with
unipolar depression or schizophrenia." [Abstract]
LT, Wang JF, Woods CM, Robb JC.
Platelet protein kinase C alpha levels
in drug-free and lithium-treated subjects with bipolar disorder.
"Recent studies suggest that protein kinase C (PKC), particularly
the alpha isoform, plays an important role in the action of lithium. There is,
however, little evidence from patients with bipolar disorder (BD) to support this
effect. The present investigation carried out comparative studies of PKC levels
in platelets obtained from BD subjects including those with and without lithium
treatment. All subjects met DSM-IV criteria for BD type I confirmed by structured
interview (SCID-IV). Levels of PKC-alpha isoform in platelets from controls and
from BD subjects were measured with immunoblotting analysis. No significant differences
were found between controls, drug-free or lithium-treated BD subjects on membrane
or cytosolic levels of PKC-alpha or in the membrane-to-cytosol ratio of this protein.
The present study suggests that levels of PKC-alpha do not change in the peripheral
tissues of BD subjects with or without lithium treatment." [Abstract]
GN, Dwivedi Y, SridharaRao J, Ren X, Janicak PG, Sharma R.
kinase C and phospholipase C activity and expression of their specific isozymes
is decreased and expression of MARCKS is increased in platelets of bipolar but
not in unipolar patients.
Neuropsychopharmacology 2002 Feb;26(2):216-28
C (PLC) and protein kinase C (PKC) are important components of the phosphoinositide
(PI) signaling system. To examine if the abnormalities observed in the PI signaling
system of patients with affective disorders, reported in previous studies, are
related to abnormalities in one or more of its components, we studied PKC, PI-PLC
activity, the expression of their specific isozymes, and expression of myristoylated
alanine-rich C-kinase substrate (MARCKS) in platelets obtained from 15 drug-free
hospitalized patients with bipolar disorder and 15 with major depressive disorder
(unipolar) and from 15 nonhospitalized normal control subjects. We observed a
significant decrease in PI-PLC and PKC activity and the expression of selective
PKC alpha, betaI, betaII, and PLC delta(1) isozymes in membrane and cytosol fraction
of platelets from bipolar but not unipolar patients. On the other hand, the level
of MARCKS was significantly increased in membrane and cytosol fraction of platelets
from patients with bipolar but not unipolar disorders. These results suggest that
alterations in PKC, PLC, and MARCKS may be involved in the pathophysiology of
bipolar illness." [Abstract]
Manji HK, Chen G.
PKC, MAP kinases
and the bcl-2 family of proteins as long-term targets for mood stabilizers.
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."
G, Masana MI, Manji HK.
Lithium regulates PKC-mediated intracellular
cross-talk and gene expression in the CNS in vivo.
Disord 2000 Sep;2(3 Pt 2):217-36
"It has become increasingly appreciated
that the long-term treatment of complex neuropsychiatric disorders like bipolar
disorder (BD) involves the strategic regulation of signaling pathways and gene
expression in critical neuronal circuits. Accumulating evidence from our laboratories
and others has identified the family of protein kinase C (PKC) isozymes as a shared
target in the brain for the long-term action of both lithium and valproate (VPA)
in the treatment of BD. In rats chronically treated with lithium at therapeutic
levels, there is a reduction in the levels of frontal cortical and hippocampal
membrane-associated PKC alpha and PKC epsilon. Using in vivO microdialysis, we
have investigated the effects of chronic lithium on the intracellular cross-talk
between PKC and the cyclic AMP (cAMP) generating system in vivo. We have found
that activation of PKC produces an increase in dialysate cAMP levels in both prefrontal
cortex and hippocampus, effects which are attenuated by chronic lithium administration.
Lithium also regulates the activity of another major signaling pathway the c-Jun
N-terminal kinase pathway--in a PKC-dependent manner. Both Li and VPA, at therapeutically
relevant concentrations, increase the DNA binding of activator protein 1 (AP-1)
family of transcription factors in cultured cells in vitro, and in rat brain ex
vivo. Furthermore, both agents increase the expression of an AP-1 driven reporter
gene, as well as the expression of several endogenous genes known to be regulated
by AP-1. Together, these results suggest that the PKC signaling pathway and PKC-mediated
gene expression may be important mediators of lithium's long-term therapeutic
effects in a disorder as complex as BD." [Abstract]
Chen, G, Manji, HK, Hawver, DB, Wright, CB, Potter,
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]
Manji HK, Etcheberrigaray R, Chen G, Olds JL.
decreases membrane-associated protein kinase C in hippocampus: selectivity for
the alpha isozyme.
J Neurochem 1993 Dec;61(6):2303-10
investigated the effects of lithium on alterations in the amount and distribution
of protein kinase C (PKC) in discrete areas of rat brain by using [3H]phorbol
12,13-dibutyrate quantitative autoradiography as well as western blotting. Chronic
administration of lithium resulted in a significant decrease in membrane-associated
PKC in several hippocampal structures, most notably the subiculum and the CA1
region. In contrast, only modest changes in [3H]phorbol 12,13-dibutyrate binding
were observed in the various other cortical and subcortical structures examined.
Immunoblotting using monoclonal anti-PKC antibodies revealed an isozyme-specific
30% decrease in hippocampal membrane-associated PKC alpha, in the absence of any
changes in the labeling of either the beta (I/II) or gamma isozymes. These changes
were observed only after chronic (4 week) treatment with lithium, and not after
acute (5 days) treatment, suggesting potential clinical relevance. Given the critical
role of PKC in regulating neuronal signal transduction, lithium's effects on PKC
in the limbic system represent an attractive molecular mechanism for its efficacy
in treating both poles of manic-depressive illness. In addition, the decreased
hippocampal membrane-associated PKC observed in the present study offers a possible
explanation for lithium-induced memory impairment." [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]
Kim HF, Weeber EJ, Sweatt JD, Stoll AL, Marangell LB.
effects of omega-3 fatty acids on protein kinase C activity in vitro.
Psychiatry 2001 Mar;6(2):246-8
"Preliminary clinical data indicate that
omega-3 fatty acids may be effective mood stabilizers for patients with bipolar
disorder. Both lithium and valproic acid are known to inhibit protein kinase C
(PKC) activity after subchronic administration in cell culture and in vivo. The
current study was undertaken to determine the effects of the omega-3 fatty acids
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on protein kinase C
phosphotransferase activity in vitro. Various concentrations of DHA, EPA, and
arachidonic acid (AA) were incubated with the catalytic domain of protein kinase
C beta from rat brain. Protein kinase C activity was measured by quantifying incorporation
of (32)P-PO(4) into a synthetic peptide substrate. Both DHA and EPA, as well as
the combination of DHA and EPA, inhibited PKC activity at concentrations as low
as 10 micromol l(-1). In contrast, arachidonic acid had no effect on PKC activity.
Thus, PKC represents a potential site of action of omega-3 fatty acids in their
effects on the treatment of bipolar disorder." [Abstract]
S, Aoki S, Watanabe S.
Different effect of desipramine on protein
kinase C in platelets between bipolar and major depressive disorders.
Clin Neurosci 1999 Feb;53(1):11-5
"Protein kinase C (PKC) activity was
investigated in platelets from affective disorder subjects and healthy volunteers.
The PKC activity of platelets incubated with desipramine was determined in vitro.
The PKC activity of the major depressive disorder subjects and healthy volunteers
was inhibited by desipramine, whereas that of the bipolar disorder subjects showed
both inhibition and activation. In addition, the base PKC activity incubation
with antidepressants of the major depressive disorder patients was significantly
higher than of the bipolar disorder patients. These preliminary results suggest
that the function of PKC may, at least in part, be associated with the mechanism
of affective disorder." [Abstract]
Gould TD, Manji HK.
Signaling networks in the pathophysiology and treatment of mood disorders.
J Psychosom Res. 2002 Aug;53(2):687-97.
"Over the past decade, the focus of research into the pathophysiology of mood
disorders (bipolar disorder and unipolar depression in particular) has shifted
from an interest in the biogenic amines to an emphasis on second messenger
systems within cells. Second messenger systems rely on cell membrane receptors
to relay information from the extracellular environment to the interior of the
cell. Within the cell, this information is processed and altered, eventually to
the point where gene and protein expression patterns are changed. There is a
preponderance of evidence implicating second messenger systems and their primary
contact with the extracellular environment, G proteins, in the pathophysiology
of mood disorders. After an introduction to G proteins and second messenger
pathways, this review focuses on the evidence implicating G proteins and two
second messenger systems-the adenylate cyclase (cyclic adenosine monophosphate,
cAMP) and phosphoinositide (protein kinase C, PKC) intracellular signaling
cascades-in the pathophysiology and treatment of bipolar disorder and unipolar
depression. Emerging evidence implicates changes in cellular resiliency,
neuroplasticity and additional cellular pathways in the pathophysiology of mood
disorders. The systems discussed within this review have been implicated in
neuroplastic processes and in modulation of many other cellular pathways, making
them likely candidates for mediators of these findings." [Abstract]