Up-regulation of immunolabeled α2A-adrenoceptors, Gi coupling proteins, and regulatory receptor kinases in the prefrontal cortex of depressed suicides

Suicide and depression are associated with an increased density of alpha(2)-adrenoceptors (radioligand receptor binding) in specific regions of the human brain. The function of these inhibitory receptors involves various regulatory proteins (G(i) coupling proteins and G protein-coupled receptor kinases, GRKs), which work in concert with the receptors, In this study we quantitated in parallel the levels of immunolabeled alpha(2A)-adrenoceptors and associated regulatory proteins in brains of suicide and depressed suicide victims, Specimens of the prefrontal cortex (Brodmann area 9) were collected from 51 suicide victims and 31 control subjects. Levels of alpha(2A)-adrenoceptors, G alpha(i1/2) proteins, and GRK 2/3 were assessed by immunoblotting techniques by using specific polyclonal antisera and the immunoreactive proteins were quantitated by densitometry. Increased levels of alpha(2A)-adrenoceptors (31-40%), G alpha(i1/12) proteins (42-63%), and membrane-associated GRK 2/3 (24-32%) were found in the prefrontal cortex of suicide victims and antidepressant-free depressed suicide victims. There were significant correlations between the levels of GRK 2/3 (dependent variable) and those of alpha(2A)-adrenoceptors and G alpha(i1/2) proteins (independent variables) in the same brain samples of suicide victims (r = 0.56, p = 0.008) and depressed suicide victims (r = 0.54, p = 0.041), Antemortem antidepressant treatment was associated with a significant reduction in the levels of G alpha(i1/2) proteins (32%), but with modest decreases in the levels of alpha(2A)-adrenoceptors (6%) and GRK 2/3 (18%) in brains of depressed suicide victims. The increased levels in concert of alpha(2A)-adrenoceptors, G alpha(i1/2) proteins, and GRK 2/3 in brains of depressed suicide victims support the existence of supersensitive alpha(2A)-adrenoceptors in subjects with major depression.