Regulation of platelet alpha 2A-adrenoceptors, Gi proteins and receptor kinases in major depression: effects of mirtazapine treatment.
Major depression is associated with the upregulation of alpha(2A)-adrenoceptors in brain tissue and blood platelets. The homologous regulation of these receptors by G-protein-coupled receptor kinases (GRKs) might play a relevant role in the pathogenesis and treatment of depression. This study was designed to assess the status of the complex alpha(2A)-adrenoceptor/Galphai/GRK 2 in the platelets of depressed patients (n=22) before and after treatment with the antidepressant mirtazapine, an antagonist at alpha(2A)-adrenoceptors (30-45 mg/day for up to 6 months). A second series of depressed suicide attempters (n=32) were also investigated to further assess the status of platelet GRK 2 and GRK 6. Platelet alpha(2A)-adrenoceptors and Galphai protein immunoreactivities were increased in depressed patients (49 and 35%) compared with matched controls. In contrast, GRK 2 content was decreased in the two series of depressed patients (27 and 28%). GRK 6 (a GRK with different properties) was found unchanged. In drug-free depressed patients, the severity of depression (behavioral ratings with two different instruments) correlated inversely with the content of platelet GRK 2 (r=-0.46, n=22, p=0.032, and r=-0.55, n=22, p=0.009). After 4-24 weeks of treatment, mirtazapine induced downregulation of platelet alpha(2A)-adrenoceptors (up to 34%) and Galphai proteins (up to 28%), and the upregulation of GRK 2 (up to 30%). The results indicate that major depression is associated with reduced platelet GRK 2, suggesting that a defect of this kinase may contribute to the observed upregulation of alpha(2A)-adrenoceptors. Moreover, treatment with mirtazapine reversed this abnormality and induced downregulation of alpha(2A)-adrenoceptor/Galphai complex. The results support a role of supersensitive alpha(2A)-adrenoceptors in the pathogenesis and treatment of major depression.
García-Sevilla
Jesús A
JA
Laboratory of Neuropharmacology, Associate Unit of the Institute of Neurobiology 'Ramón y Cajal', Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain. jesus.garcia-sevilla@hcuge.ch
Ventayol
Pedro
P
Pérez
Víctor
V
Rubovszky
Grégoire
G
Puigdemont
Dolors
D
Ferrer-Alcón
Marcel
M
Andreoli
Antonio
A
Guimón
José
J
Alvarez
Enric
E
D000328:Adult; D000704:Analysis of Variance; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D016009:Chi-Square Distribution; D017868:Cyclic AMP-Dependent Protein Kinases / Q000097:blood*; D003865:Major Depressive Disorder / Q000097:blood* / Q000188:drug therapy* / Q000523:psychology; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000097:blood*; D006801:Humans; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D000078785:Mirtazapine; D043705:Receptor, Adenosine A2A / Q000097:blood*; D013406:Suicide, Attempted / Q000706:statistics & numerical data; D051552:beta-Adrenergic Receptor Kinases
D043705:Receptor, Adenosine A2A; D008803:Mianserin; D000078785:Mirtazapine; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go