Abnormal G protein αs- and αi2-subunit mRNA expression in bipolar affective disorder

Abstract

Disturbances of events associated with intracellular signaling pathways have been suspected of involvement in the development or progression of affective disorders. Often, heterotrimeric G proteins are located at the beginning of these pathways as modulators of extracellular messages. For this reason, messenger RNA expression of three G protein ␣-subunits and of phosphatidylinositol-3 kinase (PI-3 K) regulatory subunit p85 was examined in granulocytes from patients with bipolar or unipolar affective disorder and compared to healthy controls. Messenger RNA expression of the G protein subunit ␣ q and of p85 was identical in unipolar and bipolar patients and in controls. Furthermore, mRNAs of G protein subunits ␣ s and ␣ i2 were not different in unipolar patients as compared to healthy controls. Alpha s mRNA, however, was markedly increased in bipolar patients. This increase was observed in lithiumtreated (more than 12 months) and in unmedicated patients. Elevated levels of ␣ i2 mRNA in unmedicated bipolar patients did not reach statistical significance, whereas mRNA in bipolar patients receiving lithium was significantly above controls. Finally, long-term medication of unipolar patients with lithium had no influence on ␣ i2 mRNA levels. The data reveal elevated mRNA levels of G␣ s as a robust feature of bipolar affective disorder. Moreover, despite responsiveness of ␣ i2 gene expression to cAMP-related events, no substantial upregulation of ␣ i2 mRNA was observed in bipolar patients. The lack of ␣ i2 mRNA upregulation, hence, could be an additional abnormality in these patients. Even though lithium was able to reinstate this upregulation, there was no feedback downregulation of ␣ s . This strongly supports the notion of major disturbances of the cAMP signaling system in bipolar illness.

Heterotrimeric G Proteins: Insights into the Neurobiology of Mood Disorders

“…On the contrary, a possible trait marker was proposed when increased levels of G s were found without a correlation with the pharmacological treatment of the patient [129]. Similar results have been reported in granulocytes for the mRNA levels codifying for G s [171].…”

“…The densities of 45 kDa G s have been reported to be increased in prefrontal cortex of suicide victims with major depression [36,149]. A significant decrease in both [171] PTX, pertussis toxin mRNA and protein levels of G i2 and G o , and a significant increase in levels of 45 kDa G s have been observed in prefrontal cortex of suicide subjects. These alterations were reported to be independent of the retrospective psychiatric diagnosis [49].…”

Affective disorders, antidepressant drugs and brain metabolism

“…Table 3 shows the results of experimental studies on the effects of ADs and lithium on signaling cascades in the rat brain, and [31][32][33][34][35][36][37][38] At variance with these data, a region-selective impairment of phosphoinositide hydrolysis was reported in the occipital cortex. 29 The reduction of cAMP binding 26 due to a decrease in the R subunits of cAMP-dependent protein kinase may actually increase kinase activity and protein phosphorylation at subsaturating cAMP concentrations.…”

Genetic tests of biologic systems in affective disorders

“…30 Selecting candidates based on expression data also led to the detection of associations of Gprotein-coupled receptor kinase3 (GRK3) 31 and other promising gene 32 with bipolar disorder. Altered expression level of G protein AS and AI2 subunits (GNAS, GNAI2) in the post-mortem brains from bipolar or lithium receiving subjects has also been reported, 33 although variants in the former gene are not apparently associated with bipolar disorder. 34 Recent animal studies demonstrated that chronic administration of antidepressants induces elevation of cAMP-responsive element binding protein gene (CREB1) expression- 35 and cAMP-responsive element modulator (CREM)-deficient mice showed emotional and behavioral changes.…”