Depression and the role of genes involved in dopamine metabolism and signalling

Opmeer, Esther M.; Kortekaas, Rudie; Alemán, André

doi:10.1016/j.pneurobio.2010.06.003

Cited by 88 publications

(75 citation statements)

References 253 publications

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“…DAT has been the focus of many genetic studies of psychiatric disorders, not only because of its essential role in dopaminergic neurotransmission, but also because DAT serves as an important target for prescriptive medicines, such as methylphenidate and amphetamines that are used in treatment of ADHD symptoms (21). A number of studies have found associations between common genetic variants of SLC6A3 and increased risk of psychiatric disease, but deduction of their biological implications is largely elusive (22)(23)(24). During recent years, a number of rare exonic DAT variants have been identified in patients suffering from diverse neuropsychiatric and/or neurodevelopmental disorders (25-31).…”

Section: Introductionmentioning

confidence: 99%

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Herborg

Andreassen

Berlin

et al. 2018

Journal of Biological Chemistry

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Genetic factors are known to significantly contribute to the etiology of psychiatric diseases such as attention deficit hyperactivity disorder (ADHD) and autism spectrum and bipolar disorders, but the underlying molecular processes remain largely elusive. The dopamine transporter (DAT) has received continuous attention as a potential risk factor for psychiatric disease, as it is critical for dopamine homeostasis and serves as principal target for ADHD medications. Constrain metrics for the DAT-encoding gene solute carrier family 6 member 3 (SLC6A3) indicate that missense mutations are under strong negative selection, pointing to pathophysiological outcomes when DAT function is compromised. Here, we systematically characterized six rare genetic variants of DAT (I312F, T356M, D421N, A559V, E602G, and R615C) identified in patients with neuropsychiatric disorders. We evaluated dopamine uptake and ligand interactions, along with ion coordination and electrophysiological properties, to elucidate functional phenotypes, and applied Zn 2+ exposure and a substituted cysteineaccessibility approach to identify shared structural changes. Three variants (I312F, T356M, and D421N) exhibited impaired dopamine uptake associated with changes in ligand binding, ion coordination, and distinct conformational disturbances. Remarkably, we found that all three variants displayed gain-offunction electrophysiological phenotypes. I312F mediated an increased uncoupled anion conductance previously suggested to modulate neuronal excitability. T356M and D421N both mediated a cocaine-sensitive leakage of cations, which for T356M, was potentiated by Zn 2+ , concurrent with partial functional rescue. Collectively, our findings support that gain of disruptive functions due to missense mutations in SLC6A3 may be key to understanding how dopaminergic dyshomeostasis arises in heterozygous carriers.A substantial proportion of the disease etiology of common psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder, and schizophrenia is attributed genetic components (1). The underlying neurobiological mechanisms are not clear, but dopamine disturbances are believed to constitute a central component (2-7). The allelic spectrum of these dopamine-related disorders is rapidly expanding and comprises both common variants and rare structural or exonic mutations, including de novo variants (1,(8)(9)(10)(11)(12). Moreover, an interesting overlap in the genetic architecture of psychiatric disorders has been observed, and this pleiotrophy is seen for both common and rare variants (13)(14)(15)(16)(17)(18). Despite progress, much of the genetic component remains unaccounted for, and we also have the challenge ahead of translating most of the comprehensive genetic information into an understanding of underlying biological processes, and subsequently into clinically applicable knowledge. Rare variants may provide a unique handle for obtaining new disease insights as they are expected to h...

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Section: Introductionmentioning

confidence: 99%

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Herborg

Andreassen

Berlin

et al. 2018

Journal of Biological Chemistry

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“…These results suggested that the noradrenergic system participated in the antidepressant activity of PA01. In parallel with the serotonergic and noradrenergic systems, the dopaminergic system is also suggested to be implicated in the regulation of mood, and may be an important therapeutic target [8,9]. In fact, there are currently several lines of evidence regarding the efficacy of antidepressants with dopaminergic effects in the treatment of depression [39][40][41].…”

Section: Discussionmentioning

confidence: 99%

“…The dopaminergic system plays an important role in the pathophysiology of depression [8][9][10][11]. A recent study examined effects of treatment with duloxetine, a 5-HT/NE reuptake inhibitor, in combination with the Physiology & Behavior 138 (2015) 141-149 bupropion, a DA/NE reuptake inhibitor, in a small percentage of patients diagnosed with a major depressive disorder who had not achieved symptom remission with either treatment alone.…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo characterization of PA01, a novel promising triple reuptake inhibitor

Hou

Xing

Zuo

et al. 2015

Physiology & Behavior

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“…Another study found an interaction effect between the COMT Val158Met genotype and recent stressful life events on depression onset (Mandelli et al, 2007). However, as with many of the candidate genes, findings from different studies are disparate (Opmeer et al, 2010).…”

Section: Comtmentioning

confidence: 99%

A Biopsychosocial and Long Term Perspective on Child Behavioral Problems : Impact of Risk and Resilience

Agnafors

2016

Linköping University Medical Dissertations

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Depression and the role of genes involved in dopamine metabolism and signalling

Cited by 88 publications

References 253 publications

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

In vitro and in vivo characterization of PA01, a novel promising triple reuptake inhibitor

A Biopsychosocial and Long Term Perspective on Child Behavioral Problems : Impact of Risk and Resilience

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