Increased Gαq/11 immunoreactivity in postmortem occipital cortex from patients with bipolar affective disorder

ArticleinBiological Psychiatry 41(6):649-56 · April 1997with1 Reads
DOI: 10.1016/S0006-3223(96)00113-8 · Source: PubMed
Abstract
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.
    • "The G β subunit is further subdivided into three subtypes: 1, 2, and 3 [44,45]. Significant elevations in the stimulatory G α subunit (G αs ) have been observed in peripheral blood cells and post-mortem brain tissue from bipolar depressed patients [46]. Moreover, peripheral blood cells demonstrate elevated platelet levels of G α in patients with unipolar major depression [30]. "
    [Show abstract] [Hide abstract] ABSTRACT: TheG-protein β3 gene (GNβ3) has been implicated in psychiatric illness through its effects upon intracellular transduction of several neurotransmitter receptors. Multiple studies have investigated the relationship of the C825T polymorphism of the GNβ3 gene (GNβ3 C825T) to depression and antidepressant response. However, the relationship between GNβ3 C825T and depression remains inconsistent. Therefore, here we performed a meta-analysis to investigate the role of GNβ3 C825Tin depression risk. Published case-control studies examining the association between GNβ3 C825T and depression were systematically searched for through several electronic databases (PubMed, Scopus, Science Direct, Springer, Embase, psyINFO, and CNKI). The association between GNβ3 C825T and depression risk were assessed by odd ratios (ORs) and their 95% confidence intervals (CIs) for each study. Pooled ORs were constructed for allele contrast (C versus T), homozygote (CC versus TT) model, heterozygote (CC versus CT) model, dominant model (CC + CT versus TT), and recessive (CC versus TT+CT) model. In order to evaluate possible biases, a sensitivity analysis was conducted by sequential deletion of individual studies in an attempt to assess the contribution of each individual dataset to the pooled OR. Nine studies, including 1055 depressed patients and 1325 healthy controls, were included. A significant association between GNβ3 C825Tand depression was found to exist, suggesting that the T-allele of GNβ3 C825Tcan increase susceptibility to depression. After stratification by ethnicity, the same association was found in the Asian subpopulation, but not the Caucasian subpopulation. This is the first meta-analysis to reveal a relationship between GNβ3 C825T and depression. Asian T-allele carriers of GNβ3 C825T appear to be more susceptible to depression.
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    • "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). Taken together, these studies suggest overactivation of G-protein mediated neurotransmission in BD. "
    [Show abstract] [Hide abstract] 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.
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    • "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. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Sep 2008
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