Up-regulation of immunolabeled alpha(2A)-adrenoceptors, G(i) coupling proteins, and regulatory receptor kinases in the prefrontal cortex of depressedsuicides

Suicide and depression are associated with an increased density of alpha(2) -adrenoceptors (radioligand receptor binding) in specific regions of the hu man brain. The function of these inhibitory receptors involves various regu latory proteins (G(i) coupling proteins and G protein-coupled receptor kina ses, GRKs), which work in concert with the receptors, In this study we quan titated 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 collecte d from 51 suicide victims and 31 control subjects. Levels of alpha(2A)-adre noceptors, G alpha(i1/2) proteins, and GRK 2/3 were assessed by immunoblott ing techniques by using specific polyclonal antisera and the immunoreactive proteins were quantitated by densitometry. Increased levels of alpha(2A)-a drenoceptors (31-40%), G alpha(i1/12) proteins (42-63%), and membrane-assoc iated GRK 2/3 (24-32%) were found in the prefrontal cortex of suicide victi ms and antidepressant-free depressed suicide victims. There were significan t correlations between the levels of GRK 2/3 (dependent variable) and those of alpha(2A)-adrenoceptors and G alpha(i1/2) proteins (independent variabl es) 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 al pha(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 vic tims. The increased levels in concert of alpha(2A)-adrenoceptors, G alpha(i 1/2) proteins, and GRK 2/3 in brains of depressed suicide victims support t he existence of supersensitive alpha(2A)-adrenoceptors in subjects with maj or depression.