Up-Regulation of Immunolabeled α2A-Adrenoceptors, Gi Coupling Proteins, and Regulatory Receptor Kinases in the Prefrontal Cortex of Depressed Suicides

Authors


  • Abbreviations used : DSM III-R, Diagnostic and Statistical Manual of Mental Disorders, third edition, revised ; ECL, enhanced chemiluminescence ; Gi, inhibitory guanine nucleotide binding protein ; GRK, G protein-coupled receptor kinase ; NF-L, low molecular weight neurofilament ; PMD, postmortem delay.

Address correspondence and reprint requests to Dr. J. A. García-Sevilla at Laboratori de Neurofarmacologia, Department de Biologia, Universitat de les Illes Balears, Cra Valldemossa Km 7.5, E-07071 Palma de Mallorca, Spain.

Abstract

Abstract : Suicide and depression are associated with an increased density of α2-adrenoceptors (radioligand receptor binding) in specific regions of the human brain. The function of these inhibitory receptors involves various regulatory proteins (Gi 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 α2A-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 α2A-adrenoceptors, Gα1/2 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 α2A-adrenoceptors (31-40%), Gα1/2 proteins (42-63%), and membrane-associated GRK 2/3 (24-32%) were found in the prefrontal cortex of suicide victims and antidepressantfree depressed suicide victims. There were significant correlations between the levels of GRK 2/3 (dependent variable) and those of α2A-adrenoceptors and Gα1/2 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 Gα1/2 proteins (32%), but with modest decreases in the levels of α2A-adrenoceptors (6%) and GRK 2/3 (18%) in brains of depressed suicide victims. The increased levels in concert of α2A-adrenoceptors, Gα1/2 proteins, and GRK 2/3 in brains of depressed suicide victims support the existence of supersensitive α2A-adrenoceptors in subjects with major depression.

Ancillary