Regulation of GRK 2 and 6, beta-arrestin-2 and associated proteins in the prefrontal cortex of drug-free and antidepressant drug-treated subjects with major depression.
G protein-coupled receptor kinases (GRKs) and beta-arrestin-2 play a crucial role in the regulation of neurotransmitter receptors in brain. In this study, GRK 2, GRK 6, beta-arrestin-2 and associated proteins (Gbeta 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 beta-arrestin-2, PP-2A, and Gbeta proteins were not significantly different from those in matched controls. There was a positive correlation between the immunodensities of GRK 2 and beta-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.
Grange-Midroit
Muriel
M
Clinical Research Unit, Department of Psychiatry, University of Geneva, H.U.G., Belle-Idée (Les Voirons), CH-1225 Chêne-Bourg, Geneva, Switzerland.
García-Sevilla
Jesús A
JA
Ferrer-Alcón
Marcel
M
La Harpe
Romano
R
Huguelet
Philippe
P
Guimón
José
J
D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019390:Arrestins / Q000187:drug effects* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D054768:G-Protein-Coupled Receptor Kinases; D020962:Heterotrimeric GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010749:Phosphoprotein Phosphatases / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D051552:beta-Adrenergic Receptor Kinases; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605254:ARRB2 protein, human; D000928:Antidepressive Agents; D019390:Arrestins; D017981:Receptors, Neurotransmitter; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; D010749:Phosphoprotein Phosphatases; D020962:Heterotrimeric GTP-Binding Proteins