ABNORMAL G-PROTEIN ALPHA(S)-SUBUNIT AND ALPHA(I2)-SUBUNIT MESSENGER-RNA EXPRESSION IN BIPOLAR AFFECTIVE-DISORDER

Disturbances of events associated with intracellular signaling pathway s 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 mess ages. For this reason, messenger RNA expression of three G protein alp ha-subunits and of phosphatidylinositol-3 kinase (PI-3 K) regulatory s ubunit p85 was examined in granulocytes from patients with bipolar or unipolar affective disorder and compared to healthy controls. Messenge r RNA expression of the G protein subunit alpha(q) and of p85 was iden tical in unipolar and bipolar patients and in controls. Furthermore, m RNAs of G protein subunits alpha(s) and alpha(i2) were not different i n unipolar patients as compared to healthy controls. Alpha(s) mRNA, ho wever, was markedly increased in bipolar patients. This increase was o bserved in lithium-treated (more than 12 months) and in unmedicated pa tients. Elevated levels of alpha(i2) mRNA in unmedicated bipolar patie nts did not reach statistical significance, whereas mRNA in bipolar pa tients receiving lithium was significantly above controls. Finally, lo ng-term medication of unipolar patients with lithium had no influence on alpha(i2) mRNA levels. The data reveal elevated mRNA levels of G al pha(s), as a robust feature of bipolar affective disorder. Moreover, d espite responsiveness of alpha(i2) gene expression to cAMP-related eve nts, no substantial upregulation of alpha(i2) mRNA was observed in bip olar patients. The lack of alpha(i2) mRNA upregulation, hence, could b e an additional abnormality in these patients. Even though lithium was able to reinstate this upregulation, there was no feedback downregula tion of alpha(s). This strongly supports the notion of major disturban ces of the cAMP signaling system in bipolar illness.