Neurotransmitter receptor-mediated activation of G-proteins in brains of suicide victims with mood disorders: selective supersensitivity of α2A-adrenoceptors

González-Maeso, Javier; Rodrı́guez-Puertas, Rafael; Meana, J. Javier; Garcı́a-Sevilla, Jesús A.; Guimón, José

doi:10.1038/sj.mp.4001067

Cited by 98 publications

(79 citation statements)

References 78 publications

(115 reference statements)

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“…Therefore, these results further support the existence of supersensitive a 2A -adrenoceptors in major depression (Fu et al, 2001;González-Maeso et al, 2002; see also Flügge et al, 2003). Unexpectedly and in marked contrast to previous observations in the brains of drug-free depressed suicides Grange-Midroit et al, 2003), the content of platelet GRK 2 was found reduced in drug-free depressed patients.…”

Section: Discussionsupporting

confidence: 81%

“…The antidepressant mirtazapine (Holm and Markham, 1999;Delgado et al, 2002) is a potent a 2A -adrenoceptor antagonist that enhances the release of norepinephrine (acting at a 2A -autoreceptors) and serotonin (acting at a 2 -heteroreceptors) in nerve terminals (Millan et al, 2000;Haddjeri et al, 1997). Therefore, the observed clinical efficacy and downregulation of a 2A -adrenoceptors induced by mirtazepine also support a relevant role of supersensitive a 2A -adrenoceptors in the pathogenesis of major depression (Fu et al, 2001;González-Maeso et al, 2002). Chronic antidepressant treatments have been repeatedly shown to induce downregulation and desensitization of a 2 -adrenoceptors and/or Gai proteins in the platelets of depressed patients (García-Sevilla et al, 1986, 1987, 1990Piletz et al, 1991;Gurguis et al, 1999), and in the rat Barturen and García-Sevilla, 1992;Kovachich et al, 1993;Mongeau et al, 1994;Esteban et al, 1999;Mateo et al, 2001) and human (De Paermentier et al, 1997;García-Sevilla et al, 1999) brains.…”

Section: Discussionmentioning

confidence: 98%

“…Recent functional and biochemical approaches further indicate that major depression is associated with noradrenergic dysfunction and upregulation of inhibitory a 2A/C -adrenoceptors in the brain (Callado et al, 1998;García-Sevilla et al, 1999;Fu et al, 2001;González-Maeso et al, 2002;Ordway et al, 2003). Chronic psychosocial stress in monkeys (a model of depression) has also been shown to induce persistent increases of a 2A -adrenoceptors in the brain (Flügge et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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

Garcı́a-Sevilla

Ventayol

Pérez

et al. 2003

Neuropsychopharmacol

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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.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Garcı́a-Sevilla

Ventayol

Pérez

et al. 2003

Neuropsychopharmacol

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“…In addition, higher levels of G i proteins (García-Sevilla et al, 1996b, 1999 and lower levels of adenylyl cyclase activity (Reiach et al, 1999) were reported in the platelets of depressed subjects and post-mortem brains of suicide victims who previously suffered from depression. Finally, the activity of a 2A -adrenoceptors has recently been found to be enhanced in the brains of depressed suicide victims, as determined by [ 35 S]GTPgS binding (González-Maeso et al, 2002). This is in agreement with studies demonstrating increased receptor and G i protein densities.…”

Section: Alterations In a 2a -Ar Expression In The Brains Of Suicidessupporting

confidence: 85%

Increased mRNA Expression of α2A-Adrenoceptors, Serotonin Receptors and μ-Opioid Receptors in the Brains of Suicide Victims

Escribá

Ozaita

Garcı́a-Sevilla

2004

Neuropsychopharmacol

121

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The development of new therapies for the treatment of psychiatric disorders requires an in-depth knowledge of the molecular bases underlying these pathologies, which remain largely unknown. Alterations in adrenoceptors, serotonin receptors, and other G proteincoupled receptors (GPCRs) have been associated with suicide and depression. However, to date, there is little information about mRNA expression of the GPCRs in the frontal cortex of suicide victims. Our goal was to study the expression in the brain of these receptors. For this purpose, we measured mRNA levels by RT-PCR. We found that the expressions of a 2A -adrenoceptors, 5-HT 1A , 5-HT 2A serotonin receptors, and m-opioid receptors were elevated in the post-mortem brains of these suicide victims with respect to matched controls. Moreover, in the case of a 2A -adrenoceptors (the only for which these data were available), a significant correlation was observed between the level of mRNA and protein quantified in the brain of the same subjects, indicating that protein synthesis of this receptor was not influenced by post-translational regulatory mechanisms. In addition, the degree of adrenoceptor and 5-HT receptor expressions appeared to be correlated in the brains of suicide victims and control subjects. Alterations in the expression of adrenoceptors, serotonin, and opioid receptors indicate that these signaling proteins might be related to the etiopathology of suicidal and depressive behaviors. Alternatively, such changes may represent adaptive mechanisms to compensate for other as yet unknown alterations. The results also suggest that these receptors could share common regulatory mechanisms.

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“…Several members of this family have already been implicated in the pathophysiology of psychiatric illness. [13][14][15] GPR78 was identified by virtue of its homology to orphan GPR26, which was identified in human and rat. 16,17 Rat GPR26 encodes a 317-amino-acid protein distantly related to the serotonin 5-HT5a and gastrinreleasing hormone BB2 receptors.…”

Section: Introductionmentioning

confidence: 99%

Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia

et al. 2006

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The orphan G protein-coupled receptor 78 (GPR78) gene lies within a region of chromosome 4p where we have previously shown linkage to bipolar affective disorder (BPAD) in a large Scottish family. GPR78 was screened for single-nucleotide polymorphisms (SNPs) and a linkage disequilibrium map was constructed. Six tagging SNPs were selected and tested for association on a sample of 377 BPAD, 392 schizophrenia (SCZ) and 470 control individuals. Using standard v 2 statistics and a backwards logistic regression approach to adjust for the effect of sex, SNP rs1282, located approximately 3 kb upstream of the coding region, was identified as a potentially important variant in SCZ (v 2 P = 0.044; LRT P = 0.065). When the analysis was restricted to females, the strength of association increased to an uncorrected allele P-value of 0.015 (odds ratios (OR) = 1.688, 95% confidence intervals (CI): 1.104-2.581) and uncorrected genotype P-value of 0.015 (OR = 5.991, 95% CI: 1.545-23.232). Under the recessive model, the genotype P-value improved further to 0.005 (OR = 5.618, 95% CI: 1.460-21.617) and remained significant after correcting for multiple testing (P = 0.017). No single-marker association was detected in the SCZ males, in the BPAD individuals or with any other SNP. Haplotype analysis of the case-control samples revealed several global and individual haplotypes, with P-values < 0.05, all but one of which contained SNP rs1282. After correcting for multiple testing, two haplotypes remained significant in both the female BPAD individuals (P = 0.038 and 0.032) and in the full sample of affected female individuals (P = 0.044 and 0.033). Our results provide preliminary evidence for the involvement of GPR78 in susceptibility to BPAD and SCZ in the Scottish population.

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Neurotransmitter receptor-mediated activation of G-proteins in brains of suicide victims with mood disorders: selective supersensitivity of α2A-adrenoceptors

Cited by 98 publications

References 78 publications

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

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

Increased mRNA Expression of α2A-Adrenoceptors, Serotonin Receptors and μ-Opioid Receptors in the Brains of Suicide Victims

Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia

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