cAMP Signal Transduction Abnormalities in the Pathophysiology of Mood Disorders: Contributions from Postmortem Brain Studies

Chang, Annisa; Li, Peter P.; Warsh, Jerry J.

doi:10.1007/978-1-4757-3631-1_19

Cited by 5 publications

(7 citation statements)

References 75 publications

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“…As well, protein kinase A (PKA) can modulate the PI/Ca 2 þ signaling system through the phosphorylation of several intracellular targets including receptors, G proteins, PI kinase, and phospholipase C (Supattapone et al, 1988;Hajnoczky et al, 1993;Galas and Harden, 1997). Abnormalities of the cAMP-PKA signaling cascade have also been implicated in the pathophysiology of BD and as a target of lithium action (Perez et al, 2000;Chang et al, 2002). Furthermore, the cAMP system is, in turn, subject to cross-regulation by Ca 2 þ signaling through regulation at a variety of points in the cAMP signaling cascade (Choi et al, 1993;Cooper et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Chronic Lithium Treatment Attenuates Intracellular Calcium Mobilization

Wasserman

Corson

Sibony

et al. 2004

Neuropsychopharmacol

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Elevated basal intracellular calcium (Ca 2 þ ) levels ([Ca 2 þ ] B ) in B lymphoblast cell lines (BLCLs) from bipolar I disorder (BD-I) patients implicate altered Ca 2 þ homeostasis in this illness. Chronic lithium treatment affects key proteins modulating intracellular Ca 2 þ signaling. Thus, we sought to determine if chronic exposure to therapeutic lithium concentrations also modifies intracellular Ca 2 þ homeostasis in this surrogate cellular model of signal transduction disturbances in BD. BLCLs from BD-I (N ¼ 26) and healthy subjects (N ¼ 17) were regrown from frozen stock and incubated with 0.75 mM lithium or vehicle for 24 h (acute) or 7 days (chronic). [Ca 2 þ ] B , lysophosphatidic acid (LPA)-stimulated Ca 2 þ mobilization ([Ca 2 þ ] S ), and thapsigargin-induced store-operated Ca 2 þ entry (SOCE) were determined using ratiometric fluorometry with Fura-2. Compared with vehicle, chronic lithium exposure resulted in significantly higher [Ca 2 þ ] B (F ¼ 8.47; p ¼ 0.006) in BLCLs from BD-I and healthy subjects. However, peak LPA-stimulated [Ca 2 þ ] S and SOCE were significantly reduced (F ¼ 11.1, p ¼ 0.002 and F ¼ 8.36, p ¼ 0.007, respectively). Acute lithium exposure did not significantly affect measured parameters. In summary, the effect of chronic lithium to elevate [Ca 2 þ ] B in BLCLs while attenuating both receptor-stimulated and SOCE components of intracellular Ca 2 þ mobilization in BLCLs suggests that modulation of intracellular Ca 2 þ homeostasis may be important to the therapeutic action of lithium.

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Section: Discussionmentioning

confidence: 99%

Chronic Lithium Treatment Attenuates Intracellular Calcium Mobilization

Wasserman

Corson

Sibony

et al. 2004

Neuropsychopharmacol

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“…More recently, Jang and Juhnn (2001) showed that sustained activation of the G protein‐coupled cAMP signaling system in SH‐SY5Y cells, by either expressing a constitutively activated mutant of Gαs in the cells or treating them with dibutyryl‐cAMP for 6 days, increased PKA activity and mRNA levels of all PKA R subunits and Cα subunit. Such observations suggest that the higher PKA RIIβ and Cα subunit imunoreactive levels found in post‐mortem BD brain could reflect an adaptive pattern that is the signature of a hyperactive G protein‐coupled cAMP signal transduction system as postulated to occur in BD brain (reviewed in Chang et al . 2001).…”

Section: Discussionmentioning

confidence: 99%

“…For comparison, immunoreactive levels of PKA R and C subunits were also examined in PCx, a region where no appreciable changes in cAMP signaling have been previously observed in BD compared with control subjects (Chang et al . 2001).…”

Section: Discussionmentioning

confidence: 99%

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Altered cAMP‐dependent protein kinase subunit immunolabeling in post‐mortem brain from patients with bipolar affective disorder

Chang¹,

Li²,

Warsh

2003

Journal of Neurochemistry

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Previous findings of reduced [ 3 H]cAMP binding and increased activities of cAMP-dependent protein kinase (PKA) in discrete post-mortem brain regions from patients with bipolar affective disorder (BD) suggest that PKA, the major downstream target of cAMP, is also affected in this illness. As prolonged elevation of intracellular cAMP levels can modify PKA regulatory (R) and catalytic (C) subunit levels, we sought to determine whether these PKA abnormalities are related to changes in the abundance of PKA subunits in BD brain. Using immunoblotting techniques along with PKA subunit isoform-specific polyclonal antisera, levels of PKA RIa, RIb, RIIa, RIIb and Ca subunits were measured in cytosolic and particulate fractions of temporal, frontal and parietal cortices of post-mortem brain from BD patients and matched, non-neurological, non-psychiatric controls. Immunoreactive levels of cytosolic Ca in temporal and frontal cortices, as well as that of cytosolic RIIb in temporal cortex, were significantly higher in the BD compared with the matched control brains. These changes were independent of age, post-mortem interval or pH and unrelated to ante-mortem lithium treatment or suicide. These findings strengthen further the notion that the cAMP/PKA signaling system is up-regulated in discrete cerebral cortical regions in BD.

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“…Substantial evidence from clinical and animal studies suggests that the pathophysiological basis of some subtypes of bipolar affective disorder (BD) involves disturbances of intracellular signal transduction systems Chang et al 2001). The cAMP signaling system has figured prominently among the transduction systems implicated in BD.…”

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confidence: 99%