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| Open AccessStructural basis of organic cation transporter-3 inhibition
The current work reports the structure of the human organic cation transporter 3 (OCT3 / SLC22A3) and provides the structural basis of its inhibition by two specific inhibitors, decynium-22 and corticosterone.
- Basavraj Khanppnavar
- , Julian Maier
- & Harald H. Sitte
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Article
| Open AccessStructural basis for gating mechanism of the human sodium-potassium pump
Through cryo-EM analysis, here authors reveal conformational rearrangements that are critical for the gating mechanism of the human alpha3 Na+/K+−ATPase
- Phong T. Nguyen
- , Christine Deisl
- & Beth Levine
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| Open AccessStructural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2
EAAT2 is an amino acid transporter implicated in glutamate homeostasis in brain and therapy resistance of cancer cells. Here, the authors report cryo-EM structures and reveal inhibitory mechanisms via selective inhibitor WAY213613.
- Takafumi Kato
- , Tsukasa Kusakizako
- & Osamu Nureki
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| Open AccessThe dopamine transporter antiports potassium to increase the uptake of dopamine
The dopamine transporter, DAT, controls dopamine signaling by facilitating its reuptake using the Na+ gradient as driving force. Here, the authors uncover that an antiport of K+ ions also contributes to setting the rate of DAT-mediated dopamine clearance.
- Solveig G. Schmidt
- , Mette Galsgaard Malle
- & Claus J. Loland
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| Open AccessOpponent vesicular transporters regulate the strength of glutamatergic neurotransmission in a C. elegans sensory circuit
The authors describe a vesicular transporter, VST-1, that is required in glutamatergic chemosensory neurons for chemotactic avoidance behavior in C. elegans. VST-1 antagonizes VGLUT-dependent packaging of glutamate into synaptic vesicles and determines the strength of synaptic glutamate signaling.
- Jung-Hwan Choi
- , Lauren Bayer Horowitz
- & Niels Ringstad
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Article
| Open AccessThe antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter
Vilazodone (VLZ) is a drug for the treatment of major depressive disorders that targets the serotonin transporter (SERT). Here, the authors combine pharmacology measurements and cryo-EM structural analysis to characterize VLZ binding to SERT and observe that VLZ exhibits non-competitive inhibition of serotonin transport and binds with nanomolar affinity to an allosteric site in SERT.
- Per Plenge
- , Dongxue Yang
- & Claus J. Loland
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Article
| Open AccessStructural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters
The Drosophila dopamine transporter (dDAT) is a catecholamine neurotransmitter transporter that resembles the human norepinephrine transporter (hNET). Here the authors report X-ray structures of the dDAT in substrate-free form, norepinephrine-bound form and dDAT bound to commonly prescribed chronic pain inhibitors duloxetine, milnacipran and tramadol and shed light on the structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters.
- Shabareesh Pidathala
- , Aditya Kumar Mallela
- & Aravind Penmatsa
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Article
| Open AccessMillisecond dynamics of an unlabeled amino acid transporter
Excitatory amino acid transporters (EAATs) are crucial for the removal of excitatory amino acids from the synaptic cleft. Here authors combined high-speed atomic force microscopy line-scanning with automated state assignment for the determination of transport dynamics of GltPh, a prokaryotic EAAT homologue, with millisecond temporal resolution.
- Tina R. Matin
- , George R. Heath
- & Simon Scheuring
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Article
| Open AccessGABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model
GABA transporters expressed in the striatum may affect behaviour. Here the authors investigate the contribution of GABA transporters on astrocytes to the regulation of dopamine release in the striatum, and show decreased expression of GAT-1 and GAT-3 in a mouse model of Parkinsonism.
- Bradley M. Roberts
- , Natalie M. Doig
- & Stephanie J. Cragg
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Article
| Open AccessDifferential chloride homeostasis in the spinal dorsal horn locally shapes synaptic metaplasticity and modality-specific sensitization
Inhibition in spinal nociceptive pathways is weaker and more labile in lamina I —where thermal input is primarily processed— than in lamina II that encodes predominantly high threshold mechanical input. This explains why noxious thermal input makes spinal circuits prone to catastrophic sensitization.
- Francesco Ferrini
- , Jimena Perez-Sanchez
- & Yves De Koninck
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Article
| Open AccessSubstrate-induced conformational dynamics of the dopamine transporter
The dopamine transporter is responsible for termination of neurotransmission through Na+-driven reuptake of neurotransmitter from the extracellular space. Here authors use hydrogen-deuterium exchange mass spectrometry to monitor Na+- and dopamine-induced conformational dynamics of the dopamine transporter.
- Anne Kathrine Nielsen
- , Ingvar R. Möller
- & Claus J. Loland
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Article
| Open AccessVGLUT1 functions as a glutamate/proton exchanger with chloride channel activity in hippocampal glutamatergic synapses
During neurotransmission synaptic vesicles are filled with glutamate by vesicular glutamate transporters (VGLUTs). Here, authors image intact neurons and show that in synaptic vesicles VGLUT functions as a glutamate/proton exchanger associated with a channel-like chloride conductance.
- Magalie Martineau
- , Raul E. Guzman
- & Jürgen Klingauf
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Article
| Open AccessThe sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission
The dopamine transporter (DAT), a regulator of dopamine homeostasis in the brain, and sigma-1 receptor (σ1R), an endoplasmic reticulum membrane protein, are both implicated in drug addiction. In this work, the authors investigate how σ1R modulates DAT response to methamphetamine.
- Danielle O. Sambo
- , Min Lin
- & Habibeh Khoshbouei
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Article
| Open AccessGABAA receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl−-sensitive WNK1 kinase
GABAergic transmission regulates the K+-Cl− co-transporter KCC2. Here the authors demonstrate that inhibitory transmission, via GABAA receptor and WNK signaling, regulates KCC2 expression in the membrane of hippocampal neurons.
- Martin Heubl
- , Jinwei Zhang
- & Sabine Lévi
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Article
| Open AccessSuper-resolution microscopy reveals functional organization of dopamine transporters into cholesterol and neuronal activity-dependent nanodomains
The dopamine transporter (DAT) has a crucial role in the regulation of neurotransmission. Here, the authors use super-resolution imaging to show that DAT clusters into cholesterol-dependent membrane regions that are reversibly regulated by ionotropic glutamate receptors activation.
- Troels Rahbek-Clemmensen
- , Matthew D. Lycas
- & Ulrik Gether
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Article
| Open AccessDirect PIP2 binding mediates stable oligomer formation of the serotonin transporter
The human serotonin transporter (SERT) mediates the uptake of neurotransmitters to terminate neuronal signalling. Here the authors use single-molecule imaging to get insight into the molecular origin of SERT oligomerization and their pre-set stoichiometry at the plasma membrane.
- Andreas Anderluh
- , Tina Hofmaier
- & Gerhard J. Schütz
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Article
| Open AccessCoupled binding mechanism of three sodium ions and aspartate in the glutamate transporter homologue GltTk
In neurons and glia, glutamate transporters catalyse the reuptake of this neurotransmitter by coupling it with cation transport. Here the authors combine X-ray crystallography and molecular dynamics simulations of the archeal glutamate transporter GltTkto get insight into the coupled transport mechanism.
- Albert Guskov
- , Sonja Jensen
- & Dirk Jan Slotboom
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Article
| Open AccessTransition metal ion FRET uncovers K+ regulation of a neurotransmitter/sodium symporter
The neurotransmitter transporter SERT counter transport K+ to transport serotonin. Here the authors show that the activity of the prokaryotic orthologue LeuT is also modulated by this cation, suggesting a general regulatory role for K+on neutrotrasmitter:sodium symporters function.
- Christian B. Billesbølle
- , Jonas S. Mortensen
- & Claus J. Loland
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Article
| Open AccessGenetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter
Molecular details of how antidepressant drugs bind to the human serotonin transporter are not currently clear. Here, the authors introduce photo-cross-linkers into the protein and map the binding site of several antidepressants.
- Hafsteinn Rannversson
- , Jacob Andersen
- & Kristian Strømgaard
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Article
| Open AccessA CDC42EP4/septin-based perisynaptic glial scaffold facilitates glutamate clearance
Glutamate transporters mediate neurotransmitter reuptake at glutamatergic synapses. Here the authors show that CDC42 effector protein CDC42EP4 supports efficient glutamate clearance by promoting the tethering of a glutamate transporter GLAST to perisynaptic clusters of septins in Bergmann glia.
- Natsumi Ageta-Ishihara
- , Maya Yamazaki
- & Makoto Kinoshita