Increased G alpha q/11 immunoreactivity in postmortem occipital cortex from patients with bipolar affective disorder.
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.
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ABSTRACT: OBJETIVOS: Estudos pós-mortem, farmacológicos, de neuroimagem e em modelos animais têm demonstrado uma possível associação de mecanismos de sinalização intracelular na fisiopatologia do transtorno afetivo bipolar (TAB). Esse trabalho tem como objetivo revisar os achados em neuropatologia e bioquímica celular. MÉTODOS: Foi realizada uma pesquisa ao MEDLINE, entre 1980 e 2003, tendo sido utilizados os unitermos: bipolar disorder, signaling, second messengers e postmortem, além de referências cruzadas dos artigos selecionados. RESULTADOS: uropatológicos demonstraram uma diminuição do número de células neuronais e gliais, principalmente no córtex pré-frontal de pacientes bipolares. Estudos neuroquímicos demonstraram alterações nas vias do AMPc, fosfatidilinositol, Wnt/GSK-3b e Ca++ intracelular nesses pacientes. CONCLUSÃO: Os achados de alterações neuropatológicas e neuroquímicas no TAB podem estar relacionados com a fisiopatologia deste transtorno e com os efeitos dos estabilizadores de humor. No entanto, mais estudos são necessários para esclarecer o papel das cascatas de sinalização intracelular na patogênese deste transtorno.Revista Brasileira de Psiquiatria 09/2004; 26(3):180-188. · 1.86 Impact Factor
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ABSTRACT: There is a significant gap between advances in medication for mental disorders and the present static situation concerning diagnosis and monitoring treatments in these disorders. Although significant morbidity is associated with depression, failure to appropriately diagnose individuals remains the primary obstacle to the effective management of this disorder. Heterotrimeric G proteins are a crucial point of convergence in the transmission of signals from a variety of primary messengers and their membrane receptors to their intracellular effectors. The increasing interest in the clinical perspective of altered G protein function has yielded important findings concerning the involvement of G proteins in the pathophysiology of mood disorders and in the biochemical mechanisms underlying the treatment of these disorders: 1) Lithium inhibition of β-adrenergic and muscarinic receptor-coupled G protein function was suggested as a single molecular site for both its antimanic and antidepressant therapeutic effects. Other antibipolar treatments were found to exert similar effects on G protein function. 2) Increased G protein functional and immunoreactive measures were detected in peripheral blood elements of patients with mania and in postmortem cerebral cortices of bipolar patients. 3) Reduced measures of G proteins were found in large-scale studies of lymphocytes from patients with depression and of SAD patients during winter depression. 4) Alterations in function and in quantity of both Gs and Gi are significantly correlated with the severity of depressive symptomatology. 5) Normalization of G protein measures in mood-disordered patients occurred under lithium, antidepressants, and ECT, as well as light therapy. 6) No structural or regulatory abnormalities in the gene for the Gsα subunit were found in patients with bipolar disorder. As a state-dependent marker, G protein measures might be potentially used as an aid in the biochemical diagnosis of mood disorders and for the biochemical monitoring of the response to a specific treatment. Drug Dev. Res. 50:316–323, 2000. © 2000 Wiley-Liss, Inc.Drug Development Research 07/2000; 50:316-323. · 0.87 Impact Factor