ALTERATIONS IN PHOSPHOINOSITIDE SIGNALING AND G-PROTEIN LEVELS IN DEPRESSED SUICIDE BRAIN

The function of the phosphoinositide signal transduction system and th e levels of heterotrimeric G-protein alpha-subunits were examined in p ostmortem prefrontal cortex regions (8/9) and region (10) from suicide victims with major depression and matched control subjects without ps ychiatric illness. The hydrolysis of [H-3]phosphatidylinositol (PI) st imulated by phospholipase C, GTP-gamma-S, NaF, and neurotransmitter re ceptor agonists was measured in membrane preparations from both groups . Phospholipase C-beta activity was similar in depressed suicide and c ontrol subjects in the two regions of prefrontal cortex. In prefrontal cortex (10), but not in (8/9), the GTP-gamma-S concentration-dependen t stimulation of [H-3]PI hydrolysis was significantly lower(30%) in th e depressed suicide group compared to the control group. Receptor-coup led, G-protein-mediated [H-3]PI hydrolysis induced with carbachol, his tamine, trans-1-aminocyclopentyl-1,3-dicarboxylic acid (ACPD, a glutam atergic metabotropic receptor agonist), serotonin, or 2-methylthio-ade nosine triphosphate (2mATP, a purinergic receptor agonist) in the pres ence of GTP-gamma-S stimulated equivalent responses in the two groups of subjects in each brain region. In prefrontal cortex (10) there was a 68% increase in the level of the 45 kDa subtype of Gas and in prefro ntal cortex (8/9) there was a significant decrease (21%) in the level of G alpha i2 in the depressed suicide group compared to the control g roup. Levels of other heterotrimeric G-protein alpha-subunits (G alpha q/11, G alpha i1, and G alpha o) were not different in depressed suic ide and control subjects in either brain region. Moreover, there were no differences in the levels of phospholipase C-beta or protein kinase C-alpha in the two groups of subjects in either brain region examined . These results demonstrate that in the prefrontal cortex of suicide v ictims with major depression compared to normal control subjects there is a region-specific alteration of G protein-induced activation of th e phosphoinositide signal transduction system and in the levels of G-p rotein alpha-subunits involved in cyclic AMP synthesis. These findings provide direct evidence in human brain that these two important signa l transduction systems are altered in suicide subjects with major depr ession.