Increase Gaq/11 immunoreactivity in postmortem occipital cortex from patients with bipolar affective disorder
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Biological Psychiatry
(Impact Factor: 10.26).
04/1997; 41(6):649-56. DOI: 10.1016/S0006-3223(96)00113-8
As disturbances in guanine nucleotide binding (G) protein-coupled phosphoinositide second messenger systems have been implicated in bipolar disorder, we examined whether the abundance of G alpha q/11 and phospholipase C (PLC)-beta 1 two key transducing proteins in this signaling pathway, are altered in this disorder. Compared with the controls, immunoreactive levels of G alpha q/11 were significantly elevated by 62% (p = .047) in occipital cortex of bipolar subjects. A similar increase (52%) in the PLC-beta 1 immunolabeling was also found in the occipital cortex of the bipolar subjects, but only reached marginal statistical significance (p = .07). In contrast, frontal and temporal cortex G alpha q/11 or PLC-beta 1 immunolabeling did not differ between bipolar and control subjects. Cerebral cortical immunoreactive levels of G beta 1 or G beta 2, included as a negative control, were not different between comparison groups. These findings support and extend earlier observations suggesting that disturbances in G protein-coupled second messenger signaling pathways may play an important role in the pathophysiology of bipolar affective disorder.
Available from: Stanley I Rapoport
- "Overactivation of G-protein and G-protein coupled mediated functions by serotonin (Friedman and Wang, 1996), increased muscarinic (Dilsaver, 1986; Tollefson and Senogles, 1983), and dopaminergic receptors (Pearlson et al., 1995; Wong et al., 1997) also have been reported in postmortem BD brain. These GPCRs can be coupled to multiple effectors including cytosolic phospholipase A 2 (Barak et al., 2003; Basselin et al., 2005a; Basselin et al., 2003; Bhattacharjee et al., 2005; Felder, 1995; Felder et al., 1990), phospholipase C (Mathews et al., 1997), and adenylate cyclase (Young et al., 1993). "
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ABSTRACT: Overactivation of G-protein-mediated functions and altered G-protein regulation have been reported in bipolar disorder (BD) brain. Further, drugs effective in treating BD are reported to up-regulate expression of G-protein receptor kinase (GRK) 3 in rat frontal cortex. We therefore hypothesized that some G-protein subunits and GRK levels would be reduced in the brain of BD patients. We determined protein and mRNA levels of G-protein beta and gamma subunits, GRK2, and GRK3 in post-mortem frontal cortex from 10 BD patients and 10 age-matched controls by using immunoblots and real-time RT-PCR. There were statistically significant decreases in protein and mRNA levels of G-protein subunits beta and gamma and of GRK3 in BD brain but not a significant difference in the GRK2 level. Decreased expression of G-protein subunits and of GRK3 may alter neurotransmission, leading to disturbed cognition and behaviour in BD.
Available from: Rodrigo Machado-Vieira
- "It has a heterogeneous distribution in brain, and plays a major role in the regulation of neuronal excitability, neurotransmitter release, and long-term alterations in gene expression and plasticity (Huang, 1990; MacDonald et al., 2001; Nogues, 1997; Ramakers et al., 1997). A growing body of data has also implicated dysregulation of the PKC signaling cascade in the pathophysiology of BPD (Hahn and Friedman, 1999; Jope et al., 1996; Mathews et al., 1997; Turecki et al., 1998; Wang and Friedman, 1996). Specifically, PKC overactivity has been associated with motoric hyperactivity, risk-taking behavior, and excessive hedonic drive, all of which are cardinal symptoms of mania. "
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ABSTRACT: Considerable biochemical evidence suggests that the protein kinase C (PKC) signaling cascade may be a convergent point for the actions of anti-manic agents, and that excessive PKC activation can disrupt prefrontal cortical regulation of thinking and behavior. To date, however, brain protein targets of PKC's anti-manic effects have not been fully identified. Here we showed that PKC activity was enhanced in the prefrontal cortex of animals treated with the psychostimulant amphetamine. Phosphorylation of MARCKS, a marker of PKC activity, was increased in the prefrontal cortex of animals treated with the psychostimulant amphetamine, as well as in sleep-deprived animals (another animal model of mania), but decreased in lithium-treated animals. The antidepressant imipramine, which shows pro-manic properties in patients with bipolar disorder (BPD), also enhanced phospho-MARCKS in prefrontal cortex in vivo. We further explored the functional targets of PKC in mania-associated behaviors. Neurogranin is a brain-specific, postsynaptically located PKC substrate. PKC phosphorylation of neurogranin was robustly increased by pro-manic manipulations and decreased by anti-manic agents. PKC phosphorylation of the NMDA receptor site GluN1S896 and the AMPA receptor site GluA1T840 was also enhanced in the prefrontal cortex of animals treated with the antidepressant imipramine, as well as in behaviorally sleep-deprived animals, in striking contrast to the reduced activity seen in lithium-treated animals. These results suggest that PKC may play an important role in regulating NMDA and AMPA receptor functions. The biochemical profile of the PKC pathway thus encompasses both pro- and anti-manic effects on behavior. These results suggest that PKC modulators or their intracellular targets may ultimately represent novel avenues for the development of new therapeutics for mood disorders.
Available from: ncbi.nlm.nih.gov
- ", heterogeneous groups (suicide victims without a medical diagnosis)   , or the establishment of retrospective (postmortem) diagnosis of mood disorders in suicide victims      may be the basis of certain scientific discrepancies. Thus, it has been recently reported that, opposite to schizophrenia, reaching an accurate diagnosis for mood disorders is difficult to determine using retrospective diagnosis . "
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ABSTRACT: Mood disorders such as major depression and bipolar disorder are common, severe, chronic and often life-threatening illnesses. Suicide is estimated to be the cause of death in up to approximately 10-15% of individuals with mood disorders. Alterations in the signal transduction through G protein-coupled receptor (GPCR) pathways have been reported in the etiopathology of mood disorders and the suicidal behavior. In this regard, the implication of certain GPCR subtypes such as alpha(2A)-adrenoceptor has been repeatedly described using different approaches. However, several discrepancies have been recently reported in density and functional status of the heterotrimeric G proteins both in major depression and bipolar disorder. A compilation of the most relevant research topics about the implication of heterotrimeric G proteins in the etiology of mood disorders (i.e., animal models of mood disorders, studies in peripheral tissue of depressive patients, and studies in postmortem human brain of suicide victims with mood disorders) will provide a broad perspective of this potential therapeutic target field. Proposed causes of the discrepancies reported at the level of G proteins in postmortem human brain of suicide victims will be discussed.
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