Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease

Lohr, Kelly M.; Masoud, Shababa T.; Salahpour, Ali; Miller, Gary W.

doi:10.1111/ejn.13357

Cited by 95 publications

(86 citation statements)

References 195 publications

(258 reference statements)

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“…The regulation of synaptic and extrasynaptic DA concentrations is an important process that contributes to efficient DA neurotransmission and compartmentalization (Lohr, Masoud, Salahpour, & Miller, 2017). This function is driven by the DA transporter (DAT, SLC6A3), a membrane protein located perisynaptically, where it rapidly recaptures and transports DA from the extracellular space into the cytosol of the presynaptic neuron (Sotnikova, Beaulieu, Gainetdinov, & Caron, 2006).…”

Section: Discussionmentioning

confidence: 99%

Dopamine gene methylation patterns are associated with obesity markers and carbohydrate intake

et al. 2018

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IntroductionDopamine (DA) is a neurotransmitter that regulates the rewarding and motivational processes underlying food intake and eating behaviors. This study hypothesized associations of DNA methylation signatures at genes modulating DA signaling with obesity features, metabolic profiles, and dietary intake.MethodsAn adult population within the Methyl Epigenome Network Association project was included (n = 473). DNA methylation levels in white blood cells were measured by microarray (450K). Differentially methylated genes were mapped within the dopaminergic synapse pathway using the KEGG reference database (map04728). Subsequently, network enrichment analyses were run in the pathDIP portal. Associations of methylation patterns with anthropometric markers of general (BMI) and abdominal obesity (waist circumference), the blood metabolic profile, and daily dietary intakes were screened.ResultsAfter applying a correction for multiple comparisons, 12 CpG sites were strongly associated (p < 0.0001) with BMI: cg03489495 (ITPR3), cg22851378 (PPP2R2D), cg04021127 (PPP2R2D), cg22441882 (SLC18A1), cg03045635 (DRD5), cg23341970 (ITPR2), cg13051970 (DDC), cg08943004 (SLC6A3), cg20557710 (CACNA1C), cg24085522 (GNAL), cg16846691 (ITPR2), and cg09691393 (SLC6A3). Moreover, average methylation levels of these genes differed according to the presence or absence of abdominal obesity. Pathway analyses revealed a statistically significant contribution of the aforementioned genes to dopaminergic synapse transmission (p = 4.78E−08). Furthermore, SLC18A1 and SLC6A3 gene methylation signatures correlated with total energy (p < 0.001) and carbohydrate (p < 0.001) intakes.ConclusionsThe results of this investigation reveal that methylation status on DA signaling genes may underlie epigenetic mechanisms contributing to carbohydrate and calorie consumption and fat deposition.

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Section: Discussionmentioning

confidence: 99%

Dopamine gene methylation patterns are associated with obesity markers and carbohydrate intake

et al. 2018

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“…SLC6A3 is a genetic modifier of the treatment response to l -DOPA in PD [97]. The multidrug resistance gene ( MDR1 ) C1236T polymorphism may also influence PD pharmacotherapy [98] as well as SNPs in genes encoding the dopamine transporter (DAT; SLC6A3) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2) [99]. Consequently, the personalized treatment of PD patients requires the implementation of pharmacogenetic procedures in order to optimize therapeutics (improving efficacy and safety) [9].…”

Section: Pharmacogenomicsmentioning

confidence: 99%

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Cacabelos

2017

IJMS

435

300

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Parkinson’s disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the “wearing-off phenomenon”, with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics.

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“…[41] Upon excitation, the synaptic vesicles of DAergic neurons fuse with the plasma membrane and release DA to the extracellular milieu where it can interact with extrasynaptic DA receptors.Signaling is blocked by removing DA from the extracellular space.Itcan either be recycled after reuptake by DAergic neurons by the DA transporter (DAT), or degraded by MAO, which is present in both neurons and glial cells (Figure 1). He has served as the Chairman of the European COST Chemistry Action D21 "Metalloenzymes and chemical biomimetics",a nd the coordinator of other European projects in the field of bioinorganicc hemistry.His main research interest has been the chemistry of metal enzymes involved in biological oxidations.…”

Section: Dopamine Metabolismmentioning

confidence: 99%

Dopamine, Oxidative Stress and Protein–Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases

et al. 2019

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Dopamine (DA) is the most important catecholamine in the brain, as it is the most abundant and the precursor of other neurotransmitters. Degeneration of nigrostriatal neurons of substantia nigra pars compacta in Parkinson's disease represents the best‐studied link between DA neurotransmission and neuropathology. Catecholamines are reactive molecules that are handled through complex control and transport systems. Under normal conditions, small amounts of cytosolic DA are converted to neuromelanin in a stepwise process involving melanization of peptides and proteins. However, excessive cytosolic or extraneuronal DA can give rise to nonselective protein modifications. These reactions involve DA oxidation to quinone species and depend on the presence of redox‐active transition metal ions such as iron and copper. Other oxidized DA metabolites likely participate in post‐translational protein modification. Thus, protein–quinone modification is a heterogeneous process involving multiple DA‐derived residues that produce structural and conformational changes of proteins and can lead to aggregation and inactivation of the modified proteins.

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Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease

Cited by 95 publications

References 195 publications

Dopamine gene methylation patterns are associated with obesity markers and carbohydrate intake

Dopamine gene methylation patterns are associated with obesity markers and carbohydrate intake

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Dopamine, Oxidative Stress and Protein–Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases

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