Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory

Zhang, Ying; Bertolino, Alessandro; Fazio, Leonardo; Blasi, Giuseppe; Rampino, Antonio; Romano, Raffaella; Lee, Mei Ling T.; Xiao, Tao; Papp, Audrey C.; Wang, Daqing; Sadée, Wolfgang

doi:10.1073/pnas.0707106104

Cited by 382 publications

(462 citation statements)

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“…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).…”

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confidence: 63%

“…In particular, the T allele shifts splicing from D2S to D2L, decreasing the D2S/D2L ratio relative to the G allele. This SNP has also been associated with behavior and brain activity during cognitive and emotion processing in healthy humans and in patients with schizophrenia (15,22,23). More specifically, the T allele has been associated with less efficient prefronto-striatal activity during working memory (23) and with putatively greater levels of striatal dopamine (24).…”

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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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confidence: 63%

mentioning

confidence: 99%

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 SNPs in the coding regions of genes can be synonymous (silent) or non-synonymous, with the latter causing an amino acid change leading to potential phenotypic variation [111]. However, SNPs in the non- and SRp40) could bind [112]. A physiological consequence of these SNPs is that the genetically-driven changes in D 2 dopamine receptor splicing appear to affect behaviour and working memory in humans [112].…”

Section: Mechanisms Of Alternative Splicing Of Gpcrsmentioning

confidence: 99%

“…However, SNPs in the non- and SRp40) could bind [112]. A physiological consequence of these SNPs is that the genetically-driven changes in D 2 dopamine receptor splicing appear to affect behaviour and working memory in humans [112].…”

Section: Mechanisms Of Alternative Splicing Of Gpcrsmentioning

confidence: 99%

Alternative splicing of G protein-coupled receptors: physiology and pathophysiology

Markovic

Challiss

2009

Cell. Mol. Life Sci.

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Abstract. The G protein-coupled receptors (GPCRs) are a superfamily of transmembrane receptors that have a broad distribution and can collectively recognize a diverse array of ligands. Activation or inhibition of GPCR signalling can affect many (patho)physiological processes and consequently they are a major target for existing and emerging drug therapies.A common observation has been that the pharmacological, signalling and regulatory properties of GPCRs can vary in a cell-and tissue-specific manner. Such "phenotypic" diversity might be attributable to post-translational modifications and/or association of GPCRs with accessory proteins, however, post-transcriptional mechanisms are also likely to contribute. Although, approximately 50% of GPCR genes are intronless, those that possess introns can undergo alternative splicing, generating GPCR subtype isoforms that may differ in their pharmacological, signalling and regulatory properties. In this Review we shall highlight recent research into GPCR splice-variation, and discuss the potential consequences this might have for GPCR function in health and disease.

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“…Besides, Taq IA is in linkage disequilibrium with DRD2 SNPs that affect DRD2 splicing (Zhang et al. 2007). The ANKK1/DRD2 locus has another SNP associated with brain dopaminergic function named C957T (rs6277).…”

Section: Introductionmentioning

confidence: 99%

The ANKK1/DRD2 locus is a genomic substrate for affective priming and recognition of angry faces

et al. 2015

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IntroductionAnkyrin repeat and kinase domain containing I (ANKK1) and dopamine D2 receptor (DRD2) genes have been associated with psychopathic traits in clinical samples. On the other hand, individuals high in psychopathy show reduced affective priming and deficits in facial expression recognition. We have hypothesized that these emotion‐related cognitive phenomena are associated with Taq IA (rs18000497) SNP (single nucleotide polymorphism) of the ANKK1 gene and with C957T (rs6277) SNP of the DRD2 gene.MethodsWe performed a genetic association analysis in 94 self‐reported Caucasian healthy volunteers. The participants completed 144 trials of an affective priming task, in which primes and targets were emotional words. They also had to recognize 64 facial expressions of happiness, sadness, anger, and fear in an expression recognition task. Regarding the genetic analyses, Taq IA and C957T SNPs were genotyped.ResultsWe found that the C957T SNP TT genotype was associated with a stronger priming effect and a better recognition of angry expressions. No associations were found for the Taq IA SNP. In addition, in silico analysis demonstrated that C957T SNP is a marker of a regulatory sequence at the 5′ UTR of ANKK1 gene, thus suggesting the involvement of the whole ANKK1/DRD2 locus in cognitive–emotional processing.ConclusionsThese results suggest that affective priming and recognition of angry facial expressions are endophenotypes that lie on the pathway between the ANKK1/DRD2 locus and some deviant phenotypes.

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Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory

Cited by 382 publications

References 52 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

Alternative splicing of G protein-coupled receptors: physiology and pathophysiology

The ANKK1/DRD2 locus is a genomic substrate for affective priming and recognition of angry faces

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