Special Issue "Neurotransmitter Transporters in Health and Disease"

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

Deadline for manuscript submissions: 31 October 2022 | Viewed by 1854

Special Issue Editors

Dr. Sonja Sucic
E-Mail Website
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
E-Mail Website
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
E-Mail Website1 Website2
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
E-Mail Website
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

Manuscript Submission Information

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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)

Published Papers (2 papers)

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Research

Article
An Early Disturbance in Serotonergic Neurotransmission Contributes to the Onset of Parkinsonian Phenotypes in Drosophila melanogaster
Cells 2022, 11(9), 1544; https://doi.org/10.3390/cells11091544 - 05 May 2022
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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 [...] Read more.
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, Pink1B9 mutant flies. We detected lower brain serotonin content in Pink1B9 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 Pink1B9 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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Article
Sodium Binding Stabilizes the Outward-Open State of SERT by Limiting Bundle Domain Motions
Cells 2022, 11(2), 255; https://doi.org/10.3390/cells11020255 - 12 Jan 2022
Cited by 1 | Viewed by 319
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, [...] Read more.
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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