Regulation of Akt Signaling by D2and D3Dopamine ReceptorsIn Vivo

Beaulieu, Jean‐Martin; Tirotta, Emanuele; Sotnikova, Tatyana D.; Masri, Bernard; Salahpour, Ali; Gainetdinov, Raul R.; Borrelli, Emiliana; Caron, Marc G.

doi:10.1523/jneurosci.5074-06.2007

Cited by 246 publications

(235 citation statements)

References 29 publications

(71 reference statements)

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“…However, even considering the physiological difference between lymphocytes and neurons, some speculative inferences are possible based on previous studies and on the present findings. In particular, the previously demonstrated relative greater expression of D2L in brain tissue of DRD2 rs1076560 T carriers (15), together with data indicating that D2L knock-out mice display greater AKT1 activity in the brain (28), support relevance of the genetic interaction for D2 signaling transduction in the neuron, where D2L is the main mediator of D2 signaling at the postsynaptic level (21).…”

Section: Discussionmentioning

confidence: 68%

“…26 and 29). Consistent with their preferential postsynaptic localization, another experiment has also indicated that knockout of D2L receptors is sufficient to reduce activity of this pathway (28). Moreover, other studies in mice have demonstrated that D2 but not D1 agonists impair performance at the T maze and prepulse inhibition of startle in AKT1-deficient mice (30,31).…”

mentioning

confidence: 77%

“…26). The specific relationship between D2 receptor signaling and AKT1 has been elucidated by data indicating that D2 stimulation by dopamine inhibits AKT1 signaling through dephosphorylation via the β-arrestin 2/phosphatase PP2A complex (27,28) (for review, see refs. 26 and 29).…”

mentioning

confidence: 99%

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DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Blasi

Napolitano

Ursini

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The D2/AKT1/GSK-3β signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3β proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3β, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder.A large series of experimental data indicate that dopamine D2 receptors and schizophrenia are tightly related. First, these receptors are privileged targets of antipsychotic drugs, which antagonize their activity (1). Second, previous reports have suggested association between psychosis and relatively greater D2 density in striatum, even though change is moderate (2). Third, clinical symptoms and cognitive deficits have been associated with abnormal D2 signaling (3-12). The relationship between D2 receptors and cognitive deficits in schizophrenia is also supported by previous models postulating that relatively excessive D2 signaling may lead to lower cortical signal-to-noise ratio and reduced filtering of information, as well as blocking of distracting inputs (10-12). These brain processes contribute to different higherorder cognitive functions and are strongly involved in top-down modulation of attention (13,14). Consistent with these models, previous data have suggested that attentional behavior is affected by D2 genetic variation (15). Furthermore, deficits in attentional processing are centrally implicated in schizophrenia (16,17). In fact, patients with schizophrenia performing attentional tasks have abnormal activity in the cingulate cortex, a ...

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Section: Discussionmentioning

confidence: 68%

mentioning

confidence: 77%

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DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Blasi

Napolitano

Ursini

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…An acute stimulation of dopamine D2 receptors elicits dephosphorylationinduced activation of GSK3 and vice versa (Beaulieu et al, 2004(Beaulieu et al, , 2005. D2 blockade-mediated phosphorylation of GSK3 was accompanied with the activation of Akt, suggesting that Akt may be an upstream regulator of GSK3 in D2 receptor-mediated signaling (Beaulieu et al, 2007). On the other hand, the acute stimulation of serotonin 5HT1 receptors or blockade of 5HT2 receptors produces phosphorylation-induced inhibition of GSK3 in the rodent brain (Li et al, 2004).…”

Section: Introductionmentioning

confidence: 97%

Haloperidol and clozapine differentially regulate signals upstream of glycogen synthase kinase 3 in the rat frontal cortex

Roh

Seo²,

Kim

et al. 2007

Exp Mol Med

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Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D 2 receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT2 receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3α/β and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3α/β. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D 2 -or 5HT 2 -receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.

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“…Two distinct classes of DA-responsive GPCRs, D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R), are expressed within the basal ganglia and signal through opposing G-proteindependent pathways following activation by DA (Bateup et al, 2008). Previous work from our lab also suggests that striatal D2 receptors signal in a G-protein-independent manner via the scaffolding protein barrestin-2 to modulate striatal protein kinase B (Akt) and GSK3b signaling Beaulieu et al, 2007). Genetic and/or pharmacological disruption of downstream effectors engaged by DA receptors (eg, DA-and cAMP-regulated phosphoprotein of molecular weight 32 kDa and GSK3b) robustly alters motor behavior and sensitivity to antipsychotic and psychostimulant drugs (Bateup et al, 2010;Beaulieu et al, 2004;Urs et al, 2012).…”

Section: Introductionmentioning

confidence: 82%

Selective Deletion of GRK2 Alters Psychostimulant-Induced Behaviors and Dopamine Neurotransmission

Daigle

Ferris

Gainetdinov

et al. 2014

Neuropsychopharmacol

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GRK2 is a G protein-coupled receptor kinase (GRK) that is broadly expressed and is known to regulate diverse types of receptors. GRK2 null animals exhibit embryonic lethality due to a severe developmental heart defect, which has precluded the study of this kinase in the adult brain. To elucidate the specific role of GRK2 in the brain dopamine (DA) system, we used a conditional gene knockout approach to selectively delete GRK2 in DA D1 receptor (D1R)-, DA D2 receptor (D2R)-, adenosine 2A receptor (A2AR)-, or DA transporter (DAT)-expressing neurons. Here we show that select GRK2-deficient mice display hyperactivity, hyposensitivity, or hypersensitivity to the psychomotor effects of cocaine, altered striatal signaling, and DA release and uptake. Mice with GRK2 deficiency in D2R-expressing neurons also exhibited increased D2 autoreceptor activity. These findings reveal a cell-type-specific role for GRK2 in the regulation of normal motor behavior, sensitivity to psychostimulants, dopamine neurotransmission, and D2 autoreceptor function.

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Regulation of Akt Signaling by D₂and D₃Dopamine ReceptorsIn Vivo

Cited by 246 publications

References 29 publications

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Haloperidol and clozapine differentially regulate signals upstream of glycogen synthase kinase 3 in the rat frontal cortex

Selective Deletion of GRK2 Alters Psychostimulant-Induced Behaviors and Dopamine Neurotransmission

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