ABNORMAL
INTRACELLULAR CALACIUM HOMEOSTASIS IN BIPOLAR DISORDER: DIAGNOSTIC SPECIFICITY,
MECHANISMS AND EFFECTS OF MOOD STABILIZERS
Jerry J.
Warsh
Introduction
Building
evidence implicates altered signal transduction and second messenger signaling
in the pathophysiology of bipolar disorders (BD): these disturbances may be
linked to impaired cellular resilience. The integrity of calcium (Ca2+)
signaling is critical to numerous neuronal processes such as synaptogenesis,
neuroplasticity, and neurotransmitter release. Disruption of intracellular Ca2+
homeostasis (ICH) is a pivotal transition stage in the progression to cell
death. Reports of elevated basal ([Ca2+]B) and
agonist-stimulated
intracellular Ca2+ concentrations ([Ca2+]S) in
mononuclear leukocytes, platelets and B lymphoblast cell lines (BLCLs) from BD
patients suggest that impaired ICH may be an important factor that contributes
to the processes which compromise cellular resilience and adaptive responses to
cellular stress in BD.
However, questions regarding the diagnostic specificity of ICH abnormalities,
whether they represent a trait, the underlying molecular basis for these
disturbances, the extent to which they are ameliorated by mood stabilizer
medications and whether they are demonstrable in neurons or glia remain to be
answered, and have been the focus of our ongoing research.
Methods
[Ca2+]B
was determined in BLCLs from BD I , BD II, and comparison psychiatric disorders
and healthy subjects using ratiometric fluorometry with fura-2. Lysophosphatidic
acid (LPA)-stimulated [Ca2+]S, and thapsigargin
(TG)-provoked, store-operated Ca2+ entry (SOCE) were determined in a
subset of BD I and healthy subjects. For mood-stabilizer treatment studies,
BLCLs from BD I and controls were incubated with 0.75 mM lithium, 0.5 mM
valproic acid or vehicle for 24 hours (acute) or 7 days (chronic). Protein and
mRNA levels of canonical Transient Receptor Potential (TRPC) channel types 1 and
3, putative SOCE channels, and inositol-trisphosphate receptors (IP3R;
type 3) were determined by Western blotting and quantitative PCR, respectively.
Results
BLCL [Ca2+]B
was higher (ANOVA: F=4.40, df 6,304, p=0.0003) in BD I patients (N=131) compared
with healthy (N=50; Tukey’s HSD: p=0.05), schizophrenic (N=16; p=0.02) and
non-mood disorder (N=26; p=0.004) subjects but not compared with BP-II (N=62) or
major depressive disorder (N=26) patients. BD-I patients with a positive family
history of mood disorders exhibited the highest mean BLCL [Ca2+]B.
LPA-stimulated but not TG-induced [Ca2+]S was also
significantly higher (20%) in BD-I patients compared with controls. Chronic but
not acute treatment of BLCLs with lithium or valproate attenuated (10-15%) LPA-and
TG-stimulated [Ca2+]S responses. TRPC3 immunolabeling but
not mRNA levels were significantly reduced (23%, p<0.05) in lithium-treated BLCLs from BD patients compared with controls, whereas TRPC1 protein and mRNA levels and IP3R type 3 immunolabeling were not different.
Conclusions
Elevated
BLCL [Ca2+]B shows a strong association with family
history of mood disorders in first degree relatives as well as with the
diagnosis of BD-I. Hyperactive LPA-stimulated [Ca2+]S in
BLCLs from BD patients suggest receptor-stimulated PI hydrolysis or
receptor-operated Ca2+ entry (ROCE) are enhanced in BD. Attenuation
of LPA- and TG-stimulated Ca2+ mobilization by lithium or valproate
treatment, and the effect of lithium to reduce TRPC3 levels, points to possible
abnormalities in the ROCE/SOCE apparatus in the pathophysiology of BD in
patients showing abnormal ICH, the amelioration of which may be an important
component of lithium’s molecular actions.