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Neurotransmitter Transporters in Health and Disease

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 29425

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Special Issue Editors

Dr. Sonja Sucic

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Guest Editor

Center of Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
Interests: monoamine neurotransmitter transporters; trafficking and ER export; protein folding; pharmacochaperoning; structure-function relationships; antidepressant and psychostimulant action

Dr. Lynette C. Daws

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Guest Editor

Department of Cellular and Integrative Physiology, and Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Interests: function of organic cation transporters, plasma membrane monoamine transporter, dopamine, serotonin and norepinephrine transporters, in vivo electrochemistry, behavior, depression; stress; substance use disorders; addiction; eating disorders

Dr. Ameya Sanjay Kasture

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Co-Guest Editor

Department of Neuroscience and Developmental Biology, University of Vienna, Vienna, Austria
Interests: Drosophila as a model organism to study neurological disorders; behavioral neuroscience; structural and functional aspects of monoamine transporters; pharmacochaperoning

Dr. Shreyas Bhat

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Co-Guest Editor

Department of Physics, Université de Montréal, Montréal, Canada
Interests: structure-function relationships of SLC transporters and voltage gated ion channels; electrophysiology and voltage-clamp fluorometry; trafficking of membrane proteins

Special Issue Information

Dear Colleagues,

Neurotransmitter transporters (NTTs) belong to the superfamily of solute carrier (SLC) membrane transporters. These versatile proteins play a central role in controlling neurotransmission, by mediating the rapid reuptake of neurotransmitters from the synaptic cleft into neuronal and glial cells. Structures of several NTTs have already been elucidated in different conformations by X-ray crystallography, providing important insights into ion coupling, substrate translocation, and inhibitor binding. Some NTTs are drug targets of therapeutic agents, such as antidepressants and anticonvulsants, as well as of psychostimulant drugs of abuse, such as cocaine and amphetamine. Dysfunction of NTT activity can give rise to a wide range of pathologic conditions in people. Over the last decade, ample reports in the literature have directly linked genetic mutations in NTTs to diseases including Parkinson´s/dystonia, ataxia, epilepsy, mental and intellectual disability, and disorders of the auditory, visual, and muscular systems. Some of these NTT disease variants trigger folding and trafficking defects, whereas others alter transporter structure, impairing the binding, and/or translocation of endogenous substrates. To grasp the true core of how NTTs achieve their diverse biological tasks in cells, it is essential to understand both their intricate structural features and the contingent functional consequences. In this Special Issue, we welcome both research and review articles focusing on the contemporary topics and challenges in NTT research. We place particular emphasis on the molecular basis of NTTs in disease, from the atomic level to studies in animal models, and recent discoveries shedding light on novel targets that may incite the development of effective therapeutic strategies.

Dr. Sonja Sucic
Prof. Dr. Lynette C. Daws
Dr. Ameya Sanjay Kasture
Dr. Shreyas Bhat
Guest Editors

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Keywords

NTT structure, function, and regulation
trafficking and folding mechanisms of NTTs
neurological and psychiatric disorders
disease variants in NTT genes
animal models in NTT research
novel therapeutic approaches in transporter pathologies (including compounds targeting NTTs)

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Published Papers (10 papers)

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25 pages, 4982 KiB

Open AccessArticle

Who Knew? Dopamine Transporter Activity Is Critical in Innate and Adaptive Immune Responses

by Adithya Gopinath, Phillip M. Mackie, Leah T. Phan, Rosa Mirabel, Aidan R. Smith, Emily Miller, Stephen Franks, Ohee Syed, Tabish Riaz, Brian K. Law, Nikhil Urs and Habibeh Khoshbouei

Cells 2023, 12(2), 269; https://doi.org/10.3390/cells12020269 - 10 Jan 2023

Cited by 8 | Viewed by 4678

Abstract

The dopamine transporter (DAT) regulates the dimension and duration of dopamine transmission. DAT expression, its trafficking, protein–protein interactions, and its activity are conventionally studied in the CNS and within the context of neurological diseases such as Parkinson’s Diseases and neuropsychiatric diseases such as drug addiction, attention deficit hyperactivity and autism. However, DAT is also expressed at the plasma membrane of peripheral immune cells such as monocytes, macrophages, T-cells, and B-cells. DAT activity via an autocrine/paracrine signaling loop regulates macrophage responses to immune stimulation. In a recent study, we identified an immunosuppressive function for DAT, where blockade of DAT activity enhanced LPS-mediated production of IL-6, TNF-α, and mitochondrial superoxide levels, demonstrating that DAT activity regulates macrophage immune responses. In the current study, we tested the hypothesis that in the DAT knockout mice, innate and adaptive immunity are perturbed. We found that genetic deletion of DAT (DAT^−/−) results in an exaggerated baseline inflammatory phenotype in peripheral circulating myeloid cells. In peritoneal macrophages obtained from DAT^−/− mice, we identified increased MHC-II expression and exaggerated phagocytic response to LPS-induced immune stimulation, suppressed T-cell populations at baseline and following systemic endotoxemia and exaggerated memory B cell expansion. In DAT^−/− mice, norepinephrine and dopamine levels are increased in spleen and thymus, but not in circulating serum. These findings in conjunction with spleen hypoplasia, increased splenic myeloid cells, and elevated MHC-II expression, in DAT^−/− mice further support a critical role for DAT activity in peripheral immunity. While the current study is only focused on identifying the role of DAT in peripheral immunity, our data point to a much broader implication of DAT activity than previously thought. This study is dedicated to the memory of Dr. Marc Caron who has left an indelible mark in the dopamine transporter field. Full article

(This article belongs to the Special Issue Neurotransmitter Transporters in Health and Disease)

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13 pages, 3151 KiB

Open AccessArticle

Rescue of Misfolded Organic Cation Transporter 3 Variants

by Thomas J. F. Angenoorth, Julian Maier, Stevan Stankovic, Shreyas Bhat, Sonja Sucic, Michael Freissmuth, Harald H. Sitte and Jae-Won Yang

Cells 2023, 12(1), 39; https://doi.org/10.3390/cells12010039 - 22 Dec 2022

Cited by 1 | Viewed by 2065

Abstract

Organic cation transporters (OCTs) are membrane proteins that take up monoamines, cationic drugs and xenobiotics. We previously reported novel missense mutations of organic cation transporter 3 (OCT3, SLC22A3), some with drastically impacted transport capabilities compared to wildtype. For some variants, this was due to ER retention and subsequent degradation of the misfolded transporter. For other transporter families, it was previously shown that treatment of misfolded variants with pharmacological and chemical chaperones could restore transport function to a certain degree. To investigate two potentially ER-bound, misfolded variants (D340G and R348W), we employed confocal and biochemical analyses. In addition, radiotracer uptake assays were conducted to assess whether pre-treatment with chaperones could restore transporter function. We show that pre-treatment of cells with the chemical chaperone 4-PBA (4-phenyl butyric acid) leads to increased membrane expression of misfolded variants and is associated with increased transport capacity of D340G (8-fold) and R348W (1.5 times) compared to untreated variants. We herein present proof of principle that folding-deficient SLC22 transporter variants, in particular those of OCT3, are amenable to rescue by chaperones. These findings need to be extended to other SLC22 members with corroborated disease associations. Full article

(This article belongs to the Special Issue Neurotransmitter Transporters in Health and Disease)

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17 pages, 2376 KiB

Open AccessArticle

Male DAT Val559 Mice Exhibit Compulsive Behavior under Devalued Reward Conditions Accompanied by Cellular and Pharmacological Changes

by Adele Stewart, Gwynne L. Davis, Lorena B. Areal, Maximilian J. Rabil, Vuong Tran, Felix P. Mayer and Randy D. Blakely

Cells 2022, 11(24), 4059; https://doi.org/10.3390/cells11244059 - 15 Dec 2022

Cited by 2 | Viewed by 2428

Abstract

Identified across multiple psychiatric disorders, the dopamine (DA) transporter (DAT) Ala559Val substitution triggers non-vesicular, anomalous DA efflux (ADE), perturbing DA neurotransmission and behavior. We have shown that DAT Val559 mice display a waiting impulsivity and changes in cognitive performance associated with enhanced reward motivation. Here, utilizing a within-subject, lever-pressing paradigm designed to bias the formation of goal-directed or habitual behavior, we demonstrate that DAT Val559 mice modulate their nose poke behavior appropriately to match context, but demonstrate a perseverative checking behavior. Although DAT Val559 mice display no issues with the cognitive flexibility required to acquire and re-learn a visual pairwise discrimination task, devaluation of reward evoked habitual reward seeking in DAT Val559 mutants in operant tasks regardless of reinforcement schedule. The direct DA agonist apomorphine also elicits locomotor stereotypies in DAT Val559, but not WT mice. Our observation that dendritic spine density is increased in the dorsal medial striatum (DMS) of DAT Val559 mice speaks to an imbalance in striatal circuitry that might underlie the propensity of DAT Val559 mutants to exhibit compulsive behaviors when reward is devalued. Thus, DAT Val559 mice represent a model for dissection of how altered DA signaling perturbs circuits that normally balance habitual and goal-directed behaviors. Full article

(This article belongs to the Special Issue Neurotransmitter Transporters in Health and Disease)

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15 pages, 2384 KiB

Open AccessArticle

Pharmacological Characterization of Purified Full-Length Dopamine Transporter from Drosophila melanogaster

by Ciara Frances Pugh, Brian Thomas DeVree, Solveig Gaarde Schmidt and Claus Juul Loland

Cells 2022, 11(23), 3811; https://doi.org/10.3390/cells11233811 - 28 Nov 2022

Cited by 1 | Viewed by 2150

Abstract

The dopamine transporter (DAT) is a member of the neurotransmitter:sodium symporter (NSS) family, mediating the sodium-driven reuptake of dopamine from the extracellular space thereby terminating dopaminergic neurotransmission. Our current structural understanding of DAT is derived from the resolutions of DAT from Drosophila melanogaster (dDAT). Despite extensive structural studies of purified dDAT in complex with a variety of antidepressants, psychostimulants and its endogenous substrate, dopamine, the molecular pharmacology of purified, full length dDAT is yet to be elucidated. In this study, we functionally characterized purified, full length dDAT in detergent micelles using radioligand binding with the scintillation proximity assay. We elucidate the consequences of Na⁺ and Cl⁻ binding on [³H]nisoxetine affinity and use this to evaluate the binding profiles of substrates and inhibitors to the transporter. Additionally, the technique allowed us to directly determine a equilibrium binding affinity (K_d) for [³H]dopamine to dDAT. To compare with a more native system, the affinities of specified monoamines and inhibitors was determined on dDAT, human DAT and human norepinephrine transporter expressed in COS-7 cells. With our gathered data, we established a pharmacological profile for purified, full length dDAT that will be useful for subsequent biophysical studies using dDAT as model protein for the mammalian NSS family of proteins. Full article

(This article belongs to the Special Issue Neurotransmitter Transporters in Health and Disease)

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14 pages, 2327 KiB

Open AccessArticle

Faster Serotonin Clearance in CA3 Region of Hippocampus and Antidepressant-like Effect of Decynium-22 in Juvenile Mice Are Putatively Linked to Increased Plasma Membrane Monoamine Transporter Function: Implications for Efficacy of Antidepressants in Juveniles

by Melodi A. Bowman, Jorge A. Gomez, Nathan C. Mitchell, Anne M. Wells, Melissa Vitela, Kyra M. Clarke, Rebecca E. Horton, Wouter Koek and Lynette C. Daws

Cells 2022, 11(15), 2454; https://doi.org/10.3390/cells11152454 - 8 Aug 2022

Cited by 2 | Viewed by 2118

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are less efficacious in treating depression in children than in adults. SSRIs block serotonin uptake via the high-affinity, low-capacity serotonin transporter. However, the low-affinity, high-capacity organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT) are emerging as important players in serotonin uptake. We hypothesized that OCT3 and/or PMAT are functionally upregulated in juveniles, thereby buffering SSRIs’ ability to enhance serotonergic neurotransmission. Unlike in adult mice, we found the OCT/PMAT blocker, decynium-22, to have standalone antidepressant-like effects in juveniles. Using in vivo high-speed chronoamperometry, we found that juveniles clear serotonin from the CA3 region of the hippocampus ~2-fold faster than adult mice. Cell density did not differ between ages, suggesting that faster serotonin clearance in juveniles is unrelated to faster diffusion through the extracellular matrix. Western blot and immunohistochemistry showed that juvenile mice have modestly greater expression of PMAT than adults, whereas OCT3 expression in the CA3 region of the hippocampus was similar between ages. Together, these data suggest that faster serotonin clearance and antidepressant-like effects of decynium-22 in juvenile mice may be due to functionally upregulated PMAT. Faster serotonin clearance via PMAT in juveniles may contribute to reduced therapeutic efficacy of SSRIs in children relative to adults. Full article

(This article belongs to the Special Issue Neurotransmitter Transporters in Health and Disease)

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17 pages, 2215 KiB

Open AccessArticle

Uncovering Functional Contributions of PMAT (Slc29a4) to Monoamine Clearance Using Pharmacobehavioral Tools

by Jasmin N. Beaver, Brady L. Weber, Matthew T. Ford, Anna E. Anello, Sarah K. Kassis and T. Lee Gilman

Cells 2022, 11(12), 1874; https://doi.org/10.3390/cells11121874 - 9 Jun 2022

Cited by 5 | Viewed by 2509

Abstract

Plasma membrane monoamine transporter (PMAT, Slc29a4) transports monoamine neurotransmitters, including dopamine and serotonin, faster than more studied monoamine transporters, e.g., dopamine transporter (DAT), or serotonin transporter (SERT), but with ~400–600-fold less affinity. A considerable challenge in understanding PMAT’s monoamine clearance contributions is that no current drugs selectively inhibit PMAT. To advance knowledge about PMAT’s monoamine uptake role, and to circumvent this present challenge, we investigated how drugs that selectively block DAT/SERT influence behavioral readouts in PMAT wildtype, heterozygote, and knockout mice of both sexes. Drugs typically used as antidepressants (escitalopram, bupropion) were administered acutely for readouts in tail suspension and locomotor tests. Drugs with psychostimulant properties (cocaine, D-amphetamine) were administered repeatedly to assess initial locomotor responses plus psychostimulant-induced locomotor sensitization. Though we hypothesized that PMAT-deficient mice would exhibit augmented responses to antidepressant and psychostimulant drugs due to constitutively attenuated monoamine uptake, we instead observed sex-selective responses to antidepressant drugs in opposing directions, and subtle sex-specific reductions in psychostimulant-induced locomotor sensitization. These results suggest that PMAT functions differently across sexes, and support hypotheses that PMAT’s monoamine clearance contribution emerges when frontline transporters (e.g., DAT, SERT) are absent, saturated, and/or blocked. Thus, known human polymorphisms that reduce PMAT function could be worth investigating as contributors to varied antidepressant and psychostimulant responses. Full article

(This article belongs to the Special Issue Neurotransmitter Transporters in Health and Disease)

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16 pages, 2805 KiB

Open AccessArticle

Low-Frequency Oscillations of In Vivo Ambient Extracellular Brain Serotonin

by Colby E. Witt, Sergio Mena, Lauren E. Honan, Lauren Batey, Victoria Salem, Yangguang Ou and Parastoo Hashemi

Cells 2022, 11(10), 1719; https://doi.org/10.3390/cells11101719 - 23 May 2022

Cited by 3 | Viewed by 3489

Abstract

Serotonin is an important neurotransmitter that plays a major role in many aspects of neuroscience. Fast-scan cyclic voltammetry measures fast in vivo serotonin dynamics using carbon fiber microelectrodes. More recently, fast-scan controlled-adsorption voltammetry (FSCAV) has been developed to measure slower, minute-to-minute changes in ambient extracellular serotonin. We have previously demonstrated that FSCAV measurements of basal serotonin levels give critical information regarding brain physiology and disease. In this work, we revealed the presence of low-periodicity fluctuations in serotonin levels in mouse hippocampi, measured in vivo with FSCAV. Using correlation analyses, we found robust evidence of oscillations in the basal serotonin levels, which had a period of 10 min and were not present in vitro. Under control conditions, the oscillations did not differ between male and female mice, nor do they differ between mice that underwent a chronic stress paradigm and those in the control group. After the acute administration of a selective serotonin reuptake inhibitor, we observed a shift in the frequency of the oscillations, leading us to hypothesize that the newly observed fluctuations were transporter regulated. Finally, we optimized the experimental parameters of the FSCAV to measure at a higher temporal resolution and found more pronounced shifts in the oscillation frequency, along with a decreased oscillation amplitude. We postulate that this work may serve as a potential bridge for studying serotonin/endocrine interactions that occur on the same time scale. Full article

(This article belongs to the Special Issue Neurotransmitter Transporters in Health and Disease)

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16 pages, 1859 KiB

Open AccessArticle

An Early Disturbance in Serotonergic Neurotransmission Contributes to the Onset of Parkinsonian Phenotypes in Drosophila melanogaster

by Rafaella V. Zárate, Sergio Hidalgo, Nicole Navarro, Daniela Molina-Mateo, Duxan Arancibia, Francisca Rojo-Cortés, Carlos Oliva, María Estela Andrés, Pedro Zamorano and Jorge M. Campusano

Cells 2022, 11(9), 1544; https://doi.org/10.3390/cells11091544 - 5 May 2022

Cited by 5 | Viewed by 2728

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor symptoms and dopaminergic cell loss. A pre-symptomatic phase characterized by non-motor symptoms precedes the onset of motor alterations. Two recent PET studies in human carriers of mutations associated with familial PD demonstrate an early serotonergic commitment—alteration in SERT binding—before any dopaminergic or motor dysfunction, that is, at putative PD pre-symptomatic stages. These findings support the hypothesis that early alterations in the serotonergic system could contribute to the progression of PD, an idea difficult to be tested in humans. Here, we study some components of the serotonergic system during the pre-symptomatic phase in a well-characterized Drosophila PD model, Pink1^B9 mutant flies. We detected lower brain serotonin content in Pink1^B9 flies, accompanied by reduced activity of SERT before the onset of motor dysfunctions. We also explored the consequences of a brief early manipulation of the serotonergic system in the development of motor symptoms later in aged animals. Feeding young Pink1^B9 flies with fluoxetine, a SERT blocker, prevents the loss of dopaminergic neurons and ameliorates motor impairment observed in aged mutant flies. Surprisingly, the same pharmacological manipulation in young control flies results in aged animals exhibiting a PD-like phenotype. Our findings support that an early dysfunction in the serotonergic system precedes and contributes to the onset of the Parkinsonian phenotype in Drosophila. Full article

(This article belongs to the Special Issue Neurotransmitter Transporters in Health and Disease)

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13 pages, 6325 KiB

Open AccessArticle

Sodium Binding Stabilizes the Outward-Open State of SERT by Limiting Bundle Domain Motions

by Dániel Szöllősi and Thomas Stockner

Cells 2022, 11(2), 255; https://doi.org/10.3390/cells11020255 - 12 Jan 2022

Cited by 6 | Viewed by 1934

Abstract

The human serotonin transporter (hSERT) removes the neurotransmitter serotonin from the synaptic cleft by reuptake into the presynaptic nerve terminal. A number of neurologic diseases are associated with dysfunction of the hSERT, and several medications for their treatment are hSERT blockers, including citalopram, fluoxetine, and paroxetine. The substrate transport is energized by the high concentration of external NaCl. We showed through molecular dynamics simulations that the binding of NaCl stabilized the hSERT in the substrate-binding competent conformation, which was characterized by an open access path to the substrate-binding site through the outer vestibule. Importantly, the binding of NaCl reduced the dynamics of the hSERT by decreasing the internal fluctuations of the bundle domain as well as the movement of the bundle domain relative to the scaffold domain. In contrast, the presence of only the bound chloride ion did not reduce the high domain mobility of the apo state. Full article

(This article belongs to the Special Issue Neurotransmitter Transporters in Health and Disease)

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11 pages, 3072 KiB

Open AccessReview

Dopamine Transporter Deficiency Syndrome (DTDS): Expanding the Clinical Phenotype and Precision Medicine Approaches

by Joanne Ng, Serena Barral, Simon N. Waddington and Manju A. Kurian

Cells 2023, 12(13), 1737; https://doi.org/10.3390/cells12131737 - 28 Jun 2023

Cited by 5 | Viewed by 2724

Abstract

Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is an ultrarare childhood movement disorder caused by biallelic loss-of-function mutations in the SLC6A3 gene. Advances in genomic analysis have revealed an evolving spectrum of SLC6A3-related neurological and neuropsychiatric disorders. Since the initial clinical and genetic characterisation of DTDS in 2009, there have been thirty-one published cases with a variety of protein-truncating variants (nonsense variants, splice-site changes, and deletions) and missense changes. Amino acid substitutions result in mutant proteins with impaired dopamine transporter function due to reduced transporter activity, impaired dopamine binding, reduced cell-surface expression, and aberrant posttranslational protein modification with impaired glycosylation. In this review, we provide an overview of the expanding clinical phenotype of DTDS and the precision therapies in development, including pharmacochaperones and gene therapy. Full article

(This article belongs to the Special Issue Neurotransmitter Transporters in Health and Disease)

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