Regulation of Platelet α2A-Adrenoceptors, Gi Proteins and Receptor Kinases in Major Depression: Effects of Mirtazapine Treatment

Abstract

Major depression is associated with the upregulation of a 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 a 2A -adrenoceptor/Gai/GRK 2 in the platelets of depressed patients (n ¼ 22) before and after treatment with the antidepressant mirtazapine, an antagonist at a 2A -adrenoceptors (30-45 mg/day for up to 6 months). A second series of depressed suicide attempters (n ¼ 32) were also investigated to further assess the status of platelet GRK 2 and GRK 6. Platelet a 2A -adrenoceptors and Gai 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 ¼ À0.46, n ¼ 22, p ¼ 0.032, and r ¼ À0.55, n ¼ 22, p ¼ 0.009). After 4-24 weeks of treatment, mirtazapine induced downregulation of platelet a 2A -adrenoceptors (up to 34%) and Gai 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 a 2A -adrenoceptors. Moreover, treatment with mirtazapine reversed this abnormality and induced downregulation of a 2A -adrenoceptor/Gai complex. The results support a role of supersensitive a 2A -adrenoceptors in the pathogenesis and treatment of major depression.

Cellular G Protein-Coupled Receptor Kinase Levels Regulate Sensitivity of the α2B-Adrenergic Receptor to Undergo Agonist-Induced Down-Regulation

“…Desensitization and down-regulation of the -opioid receptor during tolerance is associated with a 2-fold up-regulation of GRK2, GRK3, and ␤-arrestin2 (Hurlé, 2001). An increase in the levels of ␣ 2A -AR and a decrease in the levels of GRK2 were observed in platelets of patients suffering from major depression, and their treatment with the ␣ 2 -AR antagonist mirtazapine resulted in a 30% up-regulation of GRK2 and a 34% down-regulation of the ␣ 2A -AR (Garcia-Sevilla et al, 2004). Our data suggest that the sensitivity of the ␣ 2 -AR to undergo agonist-induced down-regulation is dramatically increased by modest changes in the level of GRK2 or GRK3.…”

G protein-coupled receptor kinases: More than just kinases and not only for GPCRs

“…Due to easy availability of blood samples from living patients (in contrast to the brain), these changes have often been used as biomarkers for pathological changes in psychiatric disorders (Elliott, 1992; Camacho and Dimsdale, 2000). The concentration of GRK2, but not GRK6, in platelets in depressed patients was decreased in parallel with the upregulation of α2A-adrenoreceptors, and the severity of depression in drug-free patients inversely correlated with the GRK2 platelet concentration (García-Sevilla et al, 2004). Treatment with antidepressant mirtazapine reduced the α2A-adrenoreceptor concentration and restored the level of GRK2.…”

The N251K functional polymorphism in the α2A-adrenoceptor gene is not associated with depression: a study in suicide completers

“…No cut is shown in any case of brain samples, which indicates that the nucleotide change inducing the creation of a new StyI-restriction site (CCAACG → CCAAGG) has not been generated α 2A -adrenoceptor agonist binding sites and adrenalineinduced aggregation are up-regulated, whereas antagonist binding sites remain unchanged (Piletz et al 1986;García-Sevilla 1989). Interestingly, antidepressant administration desensitizes in vivo α 2A -adrenoceptor-mediated responses in the rat brain (Invernizzi et al 2001;Mateo et al 2001;Mongeau et al 1994) and human platelets (García-Sevilla 1989;García-Sevilla et al 2004).…”