Regulation of GRK 2 and 6, β-arrestin-2 and associated proteins in the prefrontal cortex of drug-free and antidepressant drug-treated subjects with major depression

• Published in: Brain research. Molecular brain research. Vol. 111; no. 1; pp. 31 - 41
• Main Authors: Grange-Midroit, Muriel, Garcı́a-Sevilla, Jesús A., Ferrer-Alcón, Marcel, La Harpe, Romano, Huguelet, Philippe, Guimón, José
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 17.03.2003; Elsevier
• Subjects: Adult; Aged; Antidepressant drugs; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Arrestins - drug effects; Arrestins - metabolism; beta-Adrenergic Receptor Kinases; beta-Arrestin 2; beta-Arrestins; Biological and medical sciences; Cell Membrane - drug effects; Cell Membrane - metabolism; Cyclic AMP-Dependent Protein Kinases - drug effects; Cyclic AMP-Dependent Protein Kinases - metabolism; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - metabolism; Depressive Disorder, Major - physiopathology; Down-Regulation - drug effects; Down-Regulation - physiology; Female; G protein-coupled receptor kinases (GRK2 and GRK6); G-Protein-Coupled Receptor Kinases; Gβ protein; Heterotrimeric GTP-Binding Proteins - drug effects; Heterotrimeric GTP-Binding Proteins - metabolism; Humans; Immunohistochemistry; Major depression; Male; Medical sciences; Middle Aged; Neuropharmacology; Pharmacology. Drug treatments; Phosphoprotein Phosphatases - drug effects; Phosphoprotein Phosphatases - metabolism; Postmortem human brain; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Prefrontal Cortex - physiopathology; Protein phosphatase-2A; Protein-Serine-Threonine Kinases - drug effects; Protein-Serine-Threonine Kinases - metabolism; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Receptors, Neurotransmitter - drug effects; Receptors, Neurotransmitter - metabolism; Suicide; Up-Regulation - drug effects; Up-Regulation - physiology; β-arrestin-2; Disorders of the nervous system; Protein phosphatase-2A; Gβ protein; Postmortem human brain; Major depression; G protein-coupled receptor kinases (GRK2 and GRK6); β-arrestin-2; Suicide; Antidepressant drugs; Mood disorder; Human; Enzyme; Transferases; Central nervous system; Depression; Arrestin; Prefrontal cortex; Kinase; Antidepressant agent; Brain (vertebrata); G protein
• ISSN: 0169-328X; 1872-6941
• DOI: 10.1016/S0169-328X(02)00667-8

G protein-coupled receptor kinases (GRKs) and β-arrestin-2 play a crucial role in the regulation of neurotransmitter receptors in brain. In this study, GRK 2, GRK 6, β-arrestin-2 and associated proteins (Gβ proteins and protein phosphatase (PP)-2A) were quantitated in parallel (immunodensity with specific antibodies) in brains of depressed subjects (drug-free and antidepressant-treated) to investigate the effect of major depression and antidepressant drugs on these receptor regulatory proteins. Specimens of the prefrontal cortex (Brodmann’s area 9) were collected from 19 suicide and non-suicide depressed subjects and 13 control subjects. In drug-free ( n=9), but not in antidepressant-treated ( n=10), depressed subjects an increase in the density of membrane-associated GRK 2 (30%, n=9, P=0.005) was found compared with that in sex-, age-, and PMD-matched controls. Comparison between drug-free and antidepressant-treated depressed subjects showed that GRK 2 was reduced in membrane (39%, n=10, P=0.008) and cytosolic (44%, n=10, P=0.09) preparations after antidepressant drug treatment. In contrast, membrane-associated GRK 6 (drug-free and antidepressant-treated depressed subjects) was found unchanged when compared with that in matched controls. Similarly, the densities of β-arrestin-2, PP-2A, and Gβ proteins were not significantly different from those in matched controls. There was a positive correlation between the immunodensities of GRK 2 and β-arrestin-2 in membrane preparations ( r=0.48, n=19, P=0.04), suggesting that both proteins are regulated in a coordinated manner in brains of depressed subjects. The results of this study indicate that major depression is associated with upregulation of brain GRK 2, but not GRK 6, and that antidepressant drug treatment appears to induce downregulation of GRK 2 protein.