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Article ; Online: Special Issue in Honor of Baruch Kanner.

Grewer, Christof

2021 Volume 47, Issue 1, Page(s) 1–2

MeSH term(s)	Biomedical Research ; Cloning, Molecular ; Faculty ; GABA Plasma Membrane Transport Proteins/genetics ; GABA Plasma Membrane Transport Proteins/metabolism ; Glutamate Plasma Membrane Transport Proteins/genetics ; Glutamate Plasma Membrane Transport Proteins/metabolism ; History, 20th Century ; History, 21st Century
Chemical Substances	GABA Plasma Membrane Transport Proteins ; Glutamate Plasma Membrane Transport Proteins
Language	English
Publishing date	2021-10-06
Publishing country	United States
Document type	Biography ; Editorial ; Festschrift ; Historical Article ; Portrait
ZDB-ID	199335-5
ISSN	1573-6903 ; 0364-3190
ISSN (online)	1573-6903
ISSN	0364-3190
DOI	10.1007/s11064-021-03458-z
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Article ; Online: Functional and Kinetic Comparison of Alanine Cysteine Serine Transporters ASCT1 and ASCT2.

Wang, Jiali / Dong, Yang / Grewer, Christof

Biomolecules

2022 Volume 12, Issue 1

Abstract: Neutral amino acid transporters ASCT1 and ASCT2 are two SLC1 (solute carrier 1) family subtypes, which are specific for neutral amino acids. The other members of the SLC1 family are acidic amino acid transporters (EAATs 1-5). While the functional ... ...

Abstract	Neutral amino acid transporters ASCT1 and ASCT2 are two SLC1 (solute carrier 1) family subtypes, which are specific for neutral amino acids. The other members of the SLC1 family are acidic amino acid transporters (EAATs 1-5). While the functional similarities and differences between the EAATs have been well studied, less is known about how the subtypes ASCT1 and 2 differ in kinetics and function. Here, by performing comprehensive electrophysiological analysis, we identified similarities and differences between these subtypes, as well as novel functional properties, such as apparent substrate affinities of the inward-facing conformation (in the range of 70 μM for L-serine as the substrate). Key findings were: ASCT1 has a higher apparent affinity for Na
MeSH term(s)	Alanine/metabolism ; Amino Acid Transport System ASC/chemistry ; Amino Acid Transport System ASC/metabolism ; Cysteine ; Kinetics ; Serine/metabolism
Chemical Substances	Amino Acid Transport System ASC ; Serine (452VLY9402) ; Cysteine (K848JZ4886) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2022-01-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12010113
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Article ; Online: Shedding light on conformational dynamics of na(+)-coupled transporters.

Grewer, Christof

Biophysical journal

2014 Volume 106, Issue 8, Page(s) 1549–1550

MeSH term(s)	Animals ; Humans ; Sodium/metabolism ; Symporters/chemistry ; Symporters/metabolism
Chemical Substances	Symporters ; Sodium (9NEZ333N27)
Language	English
Publishing date	2014-04-17
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2014.02.029
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Article: Pre-steady-state Kinetic Analysis of Amino Acid Transporter SLC6A14 Reveals Rapid Turnover Rate and Substrate Translocation.

Shi, Yueyue / Wang, Jiali / Ndaru, Elias / Grewer, Christof

Frontiers in physiology

2021 Volume 12, Page(s) 777050

Abstract: SLC6A14 (solute carrier family 6 member 14) is an amino acid transporter, driven by ... ...

Abstract	SLC6A14 (solute carrier family 6 member 14) is an amino acid transporter, driven by Na
Language	English
Publishing date	2021-11-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2021.777050
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Article ; Online: Observing spontaneous, accelerated substrate binding in molecular dynamics simulations of glutamate transporters.

Wang, Jiali / Li, Peifan / Yu, Xiaozhen / Grewer, Christof

PloS one

2021 Volume 16, Issue 4, Page(s) e0250635

Abstract: Glutamate transporters are essential for removing the neurotransmitter glutamate from the synaptic cleft. Glutamate transport across the membrane is associated with elevator-like structural changes of the transport domain. These structural changes ... ...

Abstract	Glutamate transporters are essential for removing the neurotransmitter glutamate from the synaptic cleft. Glutamate transport across the membrane is associated with elevator-like structural changes of the transport domain. These structural changes require initial binding of the organic substrate to the transporter. Studying the binding pathway of ligands to their protein binding sites using molecular dynamics (MD) simulations requires micro-second level simulation times. Here, we used three methods to accelerate aspartate binding to the glutamate transporter homologue Gltph and to investigate the binding pathway. 1) Two methods using user-defined forces to prevent the substrate from diffusing too far from the binding site. 2) Conventional MD simulations using very high substrate concentrations in the 0.1 M range. The final, substrate bound states from these methods are comparable to the binding pose observed in crystallographic studies, although they show more flexibility in the side chain carboxylate function. We also captured an intermediate on the binding pathway, where conserved residues D390 and D394 stabilize the aspartate molecule. Finally, we investigated glutamate binding to the mammalian glutamate transporter, excitatory amino acid transporter 1 (EAAT1), for which a crystal structure is known, but not in the glutamate-bound state. Overall, the results obtained in this study reveal new insights into the pathway of substrate binding to glutamate transporters, highlighting intermediates on the binding pathway and flexible conformational states of the side chain, which most likely become locked in once the hairpin loop 2 closes to occlude the substrate.
MeSH term(s)	Amino Acid Transport System X-AG/chemistry ; Amino Acid Transport System X-AG/metabolism ; Aspartic Acid/chemistry ; Aspartic Acid/metabolism ; Binding Sites ; Excitatory Amino Acid Transporter 1/chemistry ; Excitatory Amino Acid Transporter 1/metabolism ; Glutamic Acid/chemistry ; Glutamic Acid/metabolism ; Humans ; Molecular Dynamics Simulation ; Protein Binding ; Substrate Specificity
Chemical Substances	Amino Acid Transport System X-AG ; Excitatory Amino Acid Transporter 1 ; Aspartic Acid (30KYC7MIAI) ; Glutamic Acid (3KX376GY7L)
Language	English
Publishing date	2021-04-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0250635
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Article ; Online: Pre-Steady-State Kinetics and Reverse Transport in Rat Glutamate Transporter EAAC1 with an Immobilized Transport Domain.

Wang, Jiali / Zielewicz, Laura / Dong, Yang / Grewer, Christof

Neurochemical research

2021 Volume 47, Issue 1, Page(s) 148–162

Abstract: Plasma membrane glutamate transporters move glutamate across the cell membrane in a process that is thought to involve elevator-like movement of the transport domain relative to the static trimerization domain. Conformational changes associated with this ...

Abstract	Plasma membrane glutamate transporters move glutamate across the cell membrane in a process that is thought to involve elevator-like movement of the transport domain relative to the static trimerization domain. Conformational changes associated with this elevator-like movement have been blocked by covalent crosslinking of cysteine pairs inserted strategically in several positions in the transporter structure, resulting in inhibition of steady-state transport activity. However, it is not known how these crosslinking restraints affect other partial reactions of the transporter that were identified based on pre-steady-state kinetic analysis. Here, we re-examine two different introduced cysteine pairs in the rat glutamate transporter EAAC1 recombinantely expressed in HEK293 cells, W440C/K268C and K64C/V419C, with respect to the molecular mechanism of their impairment of transporter function. Pre-steady-state kinetic studies of glutamate-induced partial reactions were performed using laser photolysis of caged glutamate to achieve sub-millisecond time resolution. Crosslinking of both cysteine pairs abolished steady-state transport current, as well as the majority of pre-steady-state glutamate-induced charge movements, in both forward and reverse transport mode, suggesting that it is not only the elevator-like movement associated with translocation, but also other transporter partial reactions that are inhibited. In contrast, sodium binding to the empty transporter, and glutamate-induced anion conductance were still intact after the W440C/K268C crosslink. Our results add to the previous mechanistic view of how covalent restraints of the transporter affect function and structural changes linked to individual steps in the transport cycle.
MeSH term(s)	Amino Acid Transport System X-AG/metabolism ; Animals ; Biological Transport ; Excitatory Amino Acid Transporter 3/metabolism ; Glutamate Plasma Membrane Transport Proteins/metabolism ; Glutamic Acid/metabolism ; HEK293 Cells ; Humans ; Kinetics ; Rats ; Sodium
Chemical Substances	Amino Acid Transport System X-AG ; Excitatory Amino Acid Transporter 3 ; Glutamate Plasma Membrane Transport Proteins ; Slc1a1 protein, rat ; Glutamic Acid (3KX376GY7L) ; Sodium (9NEZ333N27)
Language	English
Publishing date	2021-02-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	199335-5
ISSN	1573-6903 ; 0364-3190
ISSN (online)	1573-6903
ISSN	0364-3190
DOI	10.1007/s11064-021-03247-8
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Article ; Online: Genetically Encoded Halide Sensor-Based Fluorescent Assay for Rapid Screening of Glutamate Transport and Inhibition.

Zielewicz, Laura / Grewer, Christof

ACS sensors

2019 Volume 4, Issue 9, Page(s) 2358–2366

Abstract: Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system. Excitatory amino acid transporters (EAATs) are a family of transmembrane transporters responsible for glutamate uptake into cells, and their malfunction is related ...

Abstract	Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system. Excitatory amino acid transporters (EAATs) are a family of transmembrane transporters responsible for glutamate uptake into cells, and their malfunction is related to a variety of diseases, including neurodegenerative diseases and stroke. Screening for and developing inhibitors of EAATs as well as related transporters is a significant field of study for biomedical and pharmaceutical applications. Rapid, high-throughput methods are critical for the study of glutamate transporters, and fluorescent methods are appealing for this purpose as compared to more traditional electrophysiological methods. In this study, we present a method for studying glutamate transporters and inhibitors by utilizing a mutated version of a yellow fluorescent protein (YFP) highly sensitive to quenching by anions (mClY). We applied this YFP variant to fluorescent imaging of anion flux in HEK293 cells caused by transiently expressed excitatory amino acid carrier 1 (EAAC1) and excitatory amino acid transporter 2 (EAAT2) and its inhibition by competitive blockers. This method enables rapid identification of inhibitors and, potentially, activators of EAAT function, which is critical for glutamate transport research.
MeSH term(s)	Bacterial Proteins/genetics ; Biological Transport ; Excitatory Amino Acid Transporter 2/antagonists & inhibitors ; Excitatory Amino Acid Transporter 2/genetics ; Excitatory Amino Acid Transporter 2/metabolism ; Excitatory Amino Acid Transporter 3/antagonists & inhibitors ; Excitatory Amino Acid Transporter 3/genetics ; Excitatory Amino Acid Transporter 3/metabolism ; Glutamic Acid/metabolism ; HEK293 Cells ; Halogens/metabolism ; Humans ; Luminescent Proteins/genetics ; Optical Imaging/methods ; Time Factors
Chemical Substances	Bacterial Proteins ; Excitatory Amino Acid Transporter 2 ; Excitatory Amino Acid Transporter 3 ; Halogens ; Luminescent Proteins ; SLC1A1 protein, human ; yellow fluorescent protein, Bacteria ; Glutamic Acid (3KX376GY7L)
Language	English
Publishing date	2019-08-21
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2379-3694
ISSN (online)	2379-3694
DOI	10.1021/acssensors.9b00944
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Article ; Online: Observing spontaneous, accelerated substrate binding in molecular dynamics simulations of glutamate transporters.

Jiali Wang / Peifan Li / Xiaozhen Yu / Christof Grewer

PLoS ONE, Vol 16, Iss 4, p e

2021 Volume 0250635

Abstract	Glutamate transporters are essential for removing the neurotransmitter glutamate from the synaptic cleft. Glutamate transport across the membrane is associated with elevator-like structural changes of the transport domain. These structural changes require initial binding of the organic substrate to the transporter. Studying the binding pathway of ligands to their protein binding sites using molecular dynamics (MD) simulations requires micro-second level simulation times. Here, we used three methods to accelerate aspartate binding to the glutamate transporter homologue Gltph and to investigate the binding pathway. 1) Two methods using user-defined forces to prevent the substrate from diffusing too far from the binding site. 2) Conventional MD simulations using very high substrate concentrations in the 0.1 M range. The final, substrate bound states from these methods are comparable to the binding pose observed in crystallographic studies, although they show more flexibility in the side chain carboxylate function. We also captured an intermediate on the binding pathway, where conserved residues D390 and D394 stabilize the aspartate molecule. Finally, we investigated glutamate binding to the mammalian glutamate transporter, excitatory amino acid transporter 1 (EAAT1), for which a crystal structure is known, but not in the glutamate-bound state. Overall, the results obtained in this study reveal new insights into the pathway of substrate binding to glutamate transporters, highlighting intermediates on the binding pathway and flexible conformational states of the side chain, which most likely become locked in once the hairpin loop 2 closes to occlude the substrate.
Keywords	Medicine ; R ; Science ; Q
Subject code	500
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Design and Characterization of Prodrug-like Inhibitors for Preventing Glutamate Efflux through Reverse Transport.

Zielewicz, Laura J / Wang, Jiali / Ndaru, Elias / Maney, Brien / Yu, Xiaozhen / Albers, Thomas / Grewer, Christof

ACS chemical neuroscience

2023 Volume 14, Issue 23, Page(s) 4252–4263

Abstract: Glutamate transporters are responsible for active transport of the major excitatory neurotransmitter glutamate across the cell membrane, regulating the extracellular glutamate concentration in the mammalian brain. Extracellular glutamate levels in the ... ...

Abstract	Glutamate transporters are responsible for active transport of the major excitatory neurotransmitter glutamate across the cell membrane, regulating the extracellular glutamate concentration in the mammalian brain. Extracellular glutamate levels in the brain are usually in the submicromolar range but can increase by exocytosis, inhibition of cellular uptake, or through glutamate release by reverse transport, as well as other mechanisms, which can lead to neurodegeneration and neuronal cell death. Such conditions can be encountered upon energy deprivation during an ischemic stroke. Here, we developed acetoxymethyl (AM) ester prodrug-like derivatives of excitatory amino acid transporter (EAAT) inhibitors that permeate the cell membrane and are activated, most likely through hydrolysis by endogenous cellular esterases, to form the active EAAT inhibitor. Upon increase in external K
MeSH term(s)	Animals ; Humans ; Glutamic Acid/metabolism ; Prodrugs/pharmacology ; Biological Transport ; Amino Acid Transport System X-AG/metabolism ; Esters ; Mammals/metabolism
Chemical Substances	Glutamic Acid (3KX376GY7L) ; Prodrugs ; Amino Acid Transport System X-AG ; Esters
Language	English
Publishing date	2023-11-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.3c00651
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Article ; Online: Mechanism and potential sites of potassium interaction with glutamate transporters.

Wang, Jiali / Zhang, Kaiqi / Goyal, Puja / Grewer, Christof

The Journal of general physiology

2020 Volume 152, Issue 10

Abstract: In the mammalian glutamate transporters, countertransported intracellular K+ is essential for relocating the glutamate binding site to the extracellular side of the membrane. This K+-dependent process is believed to be rate limiting for the transport ... ...

Abstract	In the mammalian glutamate transporters, countertransported intracellular K+ is essential for relocating the glutamate binding site to the extracellular side of the membrane. This K+-dependent process is believed to be rate limiting for the transport cycle. In contrast, extracellular K+ induces glutamate release upon transporter reversal. Here, we analyzed potential K+ binding sites using molecular dynamics (MD) simulations and site-directed mutagenesis. Two candidate sites were identified by spontaneous K+ binding in MD simulations, one site (K1 site) overlapping with the Na1 Na+ binding site and the K2 site being localized under hairpin loop 2 (HP2). Mutations to conserved amino acid residues in these sites resulted in several transporters that were defective in K+-induced reverse transport and which bound K+ with reduced apparent affinity compared with the wild-type transporter. However, external K+ interaction was abolished in only one mutant transporter EAAC1D454A in the K1 site. Our results, for the first time, directly demonstrate effects of K1-site mutations on K+ binding, in contrast to previous reports on K+ binding sites based on indirect evidence. We propose that K+ binding to the K1 site is responsible for catalyzing the relocation step, whereas binding to the K2 site may have an as-of-yet unidentified regulatory function.
MeSH term(s)	Animals ; Binding Sites ; Excitatory Amino Acid Transporter 3/physiology ; Glutamic Acid ; Potassium/metabolism ; Sodium/metabolism
Chemical Substances	Excitatory Amino Acid Transporter 3 ; Glutamic Acid (3KX376GY7L) ; Sodium (9NEZ333N27) ; Potassium (RWP5GA015D)
Language	English
Publishing date	2020-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.202012577
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