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In the central nervous system (CNS), intracellular
signal transduction pathways are uniquely responsible for coordinating
the cellular response to information impinging on the cell from
multiple sources and time frames. It follows that abnormalities
in these pathways may lead to functional imbalance in multiple neurotransmitter
pathways, which could account for the diverse clinical features
found in BD, such as a recurrent course, mood fluctuations, psychotic
features, neurovegetative symptoms, and cognitive impairment. In
fact, the higher-order brain functions, such as behaviour, mood,
and cognition, are critically dependent on signal transduction processes
for their proper functioning (1). The time lag between the pharmacologic
and clinical effects of mood stabilizers also suggests that long-term
cellular and molecular events are important in the drugs’ mechanism
of action. Signal transduction pathways present researchers with
a range of targets that may be important for understanding the biological
basis of BD and its treatment. In this article, we will briefly
describe several signal transduction pathways and review studies
that have examined these systems in tissue from patients with BD.
Signal Transduction Pathways
Among the first studies to suggest disturbances in signal transduction
in patients with mood disorders were the findings of attenuated
b-adrenergic receptor–activated adenylyl cyclase (AC) activity
in peripheral cells (platelets and lymphocytes) from patients with
unipolar and bipolar depression (3–6). At the same time, no
differences were observed in the number or affinity of this type
of noradrenergic receptor in patients, compared with control subjects
(7,8). This suggested blunted responsiveness or desensitization,
rather than a diminished number of b-adrenergic receptors (7,9).
Since then, researchers have identified several signal transduction
molecules as targets of mood stabilizers and antidepressants. They
have also identified abnormalities in these pathways in samples
from patients with BD (for review see [10]). It is possible that
these drugs correct an underlying signal transduction abnormality
in patients. In the following sections, we will proceed downstream
along the signal transduction pathway, from coupling of G-proteins
to receptors, to direct measurement of second messengers, to kinases
and transcription factors, and finally, to regulation of gene expression
in nuclei. We will also briefly describe the molecular pathways
and the findings in patient samples.
G-Proteins
G-proteins are an integral
part of the intracellular signalling pathway, in that they link
receptors in the membrane to diverse intracellular effector molecules
and responses (see Figure 1).
G-proteins consist of 3 subunits: an a subunit that binds and hydrolyzes
guanosine triphosphate (GTP), and b and g subunits that are tightly
bound to one another (11). This heterogeneous protein structure
allows for the coupling of a wide variety of receptors to the same
or different signal transduction systems, leading to near infinite
combinations. Even modest changes in the levels of the G-proteins
have the potential to markedly alter the orderly progression of
events from the membrane receptors to their intracellular targets.
The interest in studying G-proteins in BD (see
Table 1) was largely prompted
by animal studies: these found that lithium attenuates the function
of several G proteins, including the stimulatory subtype Gas (12–14).
Young and others (15,16) described increased Gas (but not Gai, Gao,
or Gb) levels in frontal, temporal, and occipital cortex obtained
postmortem from subjects with BD. Further, these increases appear
to have functional relevance, because they were correlated with
the activity of AC, the major effector enzyme coupled to Gas, in
the same brain tissue samples. These findings were replicated and
also extended in another study with a different collection of brain
tissue. Using [35S]GTPgS binding, a specific binding assay for G-proteins,
and other methods to measure the function of G-protein a subunits,
the investigators found evidence to support both increased abundance
of G-proteins and increased function in the frontal cortex of subjects
with BD (17). In a much larger sample of subjects from the Stanley
Foundation Neuropathology Consortium, we recently reported that,
while there were no overall differences in Gas levels among patients
compared with control subjects, an increase was evident in subjects
not on lithium at the time of death, compared with those on the
medication (18). The treatment before death of patients in this
sample may have been more aggressive than that in earlier samples;
this may partly explain the failure to detect a difference between
the larger group of subjects with BD and control subjects.
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Studies of peripheral blood cells have largely confirmed
the above findings and have also explored the relation between G-protein
signalling and mood state. Schreiber and associates first reported
enhanced binding of [3H]Gpp(NH)p in mononuclear leukocytes (MNLs)
of patients with mania, implicating increased G-protein levels and
enhanced receptor-mediated G-protein activation in this patient
group (19). Since then, several studies have found an increase in
both level and function of G-protein subunits in manic and euthymic
states (19–22). At least 2 studies found increased Gas levels
in MNLs from unmedicated patients with bipolar depression (23,24),
whereas another suggested that the levels of this coupling G-protein
may be more directly linked to mood state, with increased levels
in mania and decreased levels in depression (20). At least 1 study
of a larger sample found that increased levels might be present
in both drug-free patients and in those on various mood stabilizing
medications (22). Studies of platelets from patients with BD have
also shown differences in G-protein levels (21,22). However, Alda
and colleagues measured Gas levels in transformed lymphoblasts from
lithium-responsive patients with BD and found no differences, compared
with control subjects (25). This suggests that either mood state
or cell type may be an important factor in determining whether Gas
levels are detectable in blood cells from patients with BD.
It has proved more difficult to identify the mechanisms responsible for observed G-protein abnormalities. Linkage studies of BD and the gene coding for Gas have yielded negative results (26–28), and, similarly, the gene-expression levels of Gas do not appear to be altered in postmortem brain tissue taken from subjects with BD (29). The mechanisms that determine G-protein subunit levels are very complex. It has yet to be determined whether G-protein abnormalities are directly involved in BD or whether they represent a secondary manifestation of dysfunction in another pathway. Without an understanding of the causes of any apparent differences in Gas levels, it has been harder to further develop the G-protein hypothesis of BD and its treatment. On the whole, G-protein studies suggest that altered Ga levels or function, or both—perhaps through increased receptor–G-protein coupling—play an important role in the biological basis of BD.
Cyclic Adenosine Monophosphate (cAMP)-Generating Pathway
Following receptor activation, G-proteins interact
with several enzymes called effectors. One well-characterized pathway
is the coupling of stimulatory or inhibitory G-protein subunits
to the enzyme AC (see Figure
2) (11). Multiple forms of AC catalyze the production of cAMP,
an important second messenger, from adenosine triphosphate (ATP).
The production of cAMP by this enzyme is balanced through its rapid
degradation by phosphodiesterases: another enzyme with multiple
intracellular subtypes (30). cAMP in turn regulates many cellular
functions, such as metabolism and gene transcription. The major
target for cAMP is yet another enzyme, cAMP-dependent protein kinase,
also known as protein kinase A (PKA). This enzyme is a critical
step in linking short-term changes in neurotransmitter signalling
to lasting neurobiological changes (see below) (31,32).
Several studies have reported that basal and
receptor-activated AC activities are increased in patients with
BD (see Table 2). These
changes may be linked to disturbances in the G-protein a subunits
(3–5,15,16,19,20,33,34) described in the previous section. Further,
the activity of this enzyme correlates significantly with treatment
or mood state: studies demonstrate decreased AC activity in subjects
with depression and in patients with euthymia that recurs after
lithium treatment (20,33,34).
As described above and reviewed elsewhere, PKA is the major target
of cAMP. PKA is a complex protein made up of regulatory (R) and
catalytic (C) subunits. A postmortem study found that [3H]cAMP binding
to the PKA (R) subunits was reduced in the cerebral cortex of patients
with BD (35), which might be due to altered synthesis or protein
degradation. This is known to occur in the presence of increased
cAMP signalling (for a review, see [36]). More recently, a postmortem
brain tissue study found that the activity of this enzyme was increased
in the temporal cortex of patients with BD (37). Subsequent analysis
of the specific PKA subunits suggests that elevated PKA activity
in BD results from a state–related imbalance in the specific PKA
subunits (38). Several studies with large numbers of patients with
BD in various mood states before and after treatment, have also
found evidence of increased PKA levels and activity with increased
levels of several downstream markers in peripheral cells (39). These
postmortem brain tissue findings are interesting, and suggest that
numerous components of the G-protein–coupled, cAMP signalling pathway
are activated in patients with BD (38,40,41).
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