Abnormal G protein α_s- and α_i2-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 α-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 α_q and of p85 was identical in unipolar and bipolar patients and in controls. Furthermore, mRNAs of G protein subunits α_s and α_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 lithium-treated (more than 12 months) and in unmedicated patients. Elevated levels of α_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 α_i2 mRNA levels. The data reveal elevated mRNA levels of Gα_s as a robust feature of bipolar affective disorder. Moreover, despite responsiveness of α_i2 gene expression to cAMP-related events, no substantial upregulation of α_i2 mRNA was observed in bipolar patients. The lack of α_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 α_s. This strongly supports the notion of major disturbances of the cAMP signaling system in bipolar illness.