Review
Neurosciences
Peter Kovermann, Miriam Engels, Frank Mueller, Christoph Fahlke
Summary: Excitatory amino acid transporters (EAATs) play a crucial role in optimizing the temporal resolution and energy demand of excitatory synapses. In addition to their primary transport function, EAATs also function as anion channels. Recent research has shed light on the physiological and pathophysiological roles of EAAT anion channels.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Article
Neurosciences
Iris Alvarez-Merz, Ioulia Fomitcheva, Jeremy Sword, Jesus M. Hernandez-Guijo, Jose M. Solis, Sergei A. Kirov
Summary: In hypoxic injury, astroglial swelling induced by the accumulation of non-excitatory amino acids (AA) and release of excitotoxins through antiporters and VRAC may exacerbate neuronal injury.
Article
Biochemistry & Molecular Biology
Natasha J. Freidman, Chelsea Briot, Renae M. Ryan
Summary: This study found that the compound GPNA can activate the Cl- conductance of ASCT2 without undergoing the transport cycle. This is a previously unreported phenomenon for inhibitors of the solute carrier 1A family. Additionally, GPNA was found to inhibit several excitatory amino acid transporters. These findings raise questions about the anticancer mechanisms of GPNA.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Biao Qiu, Doreen Matthies, Eva Fortea, Zhiheng Yu, Olga Boudker
Summary: The study reveals the structure and operation mechanism of hEAAT3, suggesting it operates by an elevator mechanism involving three functionally independent subunits. The substrate-binding site near the cytoplasm has remarkably low affinity for the substrate, facilitating rapid substrate release and transport turnover. The mechanism of coupled uptake of sodium ions and substrate is conserved across evolutionarily distant families, augmented by coupling to protons in EAATs, and a mechanism involving a conserved glutamate residue mediates proton symport.
Article
Physiology
Kusumika Saha, Jae-Won Yang, Tina Hofmaier, SanthoshKannan Venkatesan, Thomas Steinkellner, Oliver Kudlacek, Sonja Sucic, Michael Freissmuth, Harald H. Sitte
Summary: This study identified the involvement of ARFGAP1 and ARF6 in the endocytosis of EAAT3, with ARFGAP1 utilizing its GAP activity and F508 to promote recycling of EAAT3. Additionally, a motif in the C-terminus of EAAT3 was found to regulate its endocytosis. These findings suggest a multifactorial regulation of EAAT3 endocytosis by ARFGAP1, highlighting the importance of the C-terminus in this process.
FRONTIERS IN PHYSIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Soojung Lee, Jason Lin, Inyeong Choi
Summary: This study discovered that the selectivity of bicarbonate in NBCe1 is determined by avoiding a specific charge interaction in the ion binding site, rather than maintaining such an interaction.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Zi Wen, Guang Xia, Chi Liang, Xinxing Wang, Junjie Huang, Lina Zhang, Dongyong Shan, Song Wu, Xu Cao
Summary: This study explored the mechanism of ferroptosis resistance in senescent chondrocytes and found that hyperactivation of ferroptosis metabolism was a prominent feature in these cells. However, senescent chondrocytes were able to survive and resist ferroptosis-induced cell death due to overexpression of the membrane protein EAAT1, which increased intracellular Glu levels and activated the glutathione system.
ANTIOXIDANTS & REDOX SIGNALING
(2023)
Article
Biochemistry & Molecular Biology
Shashank Pant, Qianyi Wu, Renae Ryan, Emad Tajkhorshid
Summary: EAATs, belonging to the SLC1A family of glutamate transporters, have been shown to activate chloride ion channels during transport. Molecular dynamics simulations in hEAAT1 reveal a chloride-conducting conformation, shedding light on the dual functionality of active transport and passive chloride permeation in human neurotransmitter transporters, a mechanism common across the SLC1A family.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Multidisciplinary Sciences
Jie Shen, Yongting Gu, Lingjie Ke, Qiuping Zhang, Yin Cao, Yuchao Lin, Zhen Wu, Caisheng Wu, Yuguang Mu, Yun-Long Wu, Changliang Ren, Huaqiang Zeng
Summary: Cholesterol-enhanced pore formation is an evolutionary mechanism utilized by cholesterol-free bacterial cells to specifically target cholesterol-rich eukaryotic cells. Researchers have developed a class of artificial cholesterol-dependent nanopores that can be modulated by cholesterol levels to control pore formation and channel activity. The most active channel has a nano-sized cavity, allowing transportation of nanometer-sized molecules and displaying potent anticancer activity against human hepatocellular carcinomas.
NATURE COMMUNICATIONS
(2022)
Article
Geriatrics & Gerontology
Bing Leng, Hairong Sun, Mengfan Li, Junwu Zhao, Xiaoxiao Liu, Ran Yao, Tengqun Shen, Zhenguang Li, Jinbiao Zhang
Summary: This study found that Parkinson's disease (PD) patients with rapid eye movement (REM) sleep behavior disorder (RBD) experience a greater decline in cognitive function. Blood neuroexosomal EAAT-2 levels are associated with cognitive decline in PD patients with RBD.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Article
Chemistry, Medicinal
Sanjay Das, Artem V. Trubnikov, Anton M. Novoselov, Alexander V. Kurkin, Joris Beld, Andrea Altieri, Sandhya Kortagere
Summary: Excitotoxicity in the brain is a causal factor in neurological and neurodegenerative disorders. The design and optimization of GTS467 and GTS511, activators of EAAT2 with low nanomolar efficacy, show potential for treating excitotoxicity-induced neurological disorders.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Piao Zhao, Cheng Tang, Yuqin Yang, Zhen Xiao, Samantha Perez-Miller, Heng Zhang, Guoqing Luo, Hao Liu, Yaqi Li, Qingyi Liao, Fan Yang, Hao Dong, Rajesh Khanna, Zhonghua Liu
Summary: This study reveals the proton gating and protonation-independent voltage gating mechanisms of the PAC channel, using its unique bifunctional modulator C77304, with implications for drug development.
Article
Multidisciplinary Sciences
Zhenglai Zhang, Huiwen Chen, Ze Geng, Zhuoya Yu, Hang Li, Yanli Dong, Hongwei Zhang, Zhuo Huang, Juquan Jiang, Yan Zhao
Summary: In this study, cryo-EM structures of human EAAT2 in complexes with glutamate or selective inhibitor WAY-213613 were reported, providing important insights into substrate recognition and selective inhibition.
NATURE COMMUNICATIONS
(2022)
Article
Psychiatry
Samara J. Brown, Amelia M. Brown, Tertia D. Purves-Tyson, Xu-Feng Huang, Kelly A. Newell, Cynthia Shannon Weickert
Summary: This study suggests that alterations in the kynurenine pathway may contribute to the development of depression. The increased gene expression of enzymes in the kynurenine pathway indicates an activation of the kynurenic acid arm, possibly related to astrocyte response in depression. These findings point to dysfunction of the kynurenine pathway and its potential role in glutamate dysfunction in depression.
JOURNAL OF PSYCHIATRIC RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Claudia Alleva, Jan-Philipp Machtens, Daniel Kortzak, Ingo Weyand, Christoph Fahlke
Summary: Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and its transport is facilitated by the excitatory amino acid transporters (EAATs). These transporters utilize a complex stoichiometry to accumulate glutamate against concentration gradients and are also selective channels that open and close during the transport cycle. Recent research has uncovered the molecular mechanisms of coupled transport, substrate selectivity, and anion conduction in EAAT glutamate transporters, emphasizing the hairpin 2 gate as a key component in these functions.
NEUROCHEMICAL RESEARCH
(2022)
Article
Neurosciences
Stefan A. Berghoff, Lena Spieth, Ting Sun, Leon Hosang, Lennart Schlaphoff, Constanze Depp, Tim Duking, Jan Winchenbach, Jonathan Neuber, David Ewers, Patricia Scholz, Franziska van der Meer, Ludovico Cantuti-Castelvetri, Andrew O. Sasmita, Martin Meschkat, Torben Ruhwedel, Wiebke Mobius, Roman Sankowski, Marco Prinz, Inge Huitinga, Michael W. Sereda, Francesca Odoardi, Till Ischebeck, Mikael Simons, Christine Stadelmann-Nessler, Julia M. Edgar, Klaus-Armin Nave, Gesine Saher
Summary: The study reveals that sterol synthesis in microglia/macrophages is crucial for resolving inflammation and inducing remyelination in the repair of demyelinated lesions in multiple sclerosis (MS), with desmosterol activating LXR signaling as a key mechanism.
NATURE NEUROSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Claudia Alleva, Jan-Philipp Machtens, Daniel Kortzak, Ingo Weyand, Christoph Fahlke
Summary: Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and its transport is facilitated by the excitatory amino acid transporters (EAATs). These transporters utilize a complex stoichiometry to accumulate glutamate against concentration gradients and are also selective channels that open and close during the transport cycle. Recent research has uncovered the molecular mechanisms of coupled transport, substrate selectivity, and anion conduction in EAAT glutamate transporters, emphasizing the hairpin 2 gate as a key component in these functions.
NEUROCHEMICAL RESEARCH
(2022)
Article
Chemistry, Physical
Andrei Y. Kostritskii, Claudia Alleva, Saskia Coenen, Jan-Philipp Machtens
Summary: The tool g_elpot utilizes the smooth particle mesh Ewald method to quantify the electrostatics of biomolecules by calculating potential within water molecules that are explicitly present in biomolecular MD simulations. It can extract the global distribution of the electrostatic potential from MD trajectories and measure its time course in functionally important regions of a biomolecule, providing a deeper understanding of its role in biomolecular processes.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2021)
Article
Multidisciplinary Sciences
Andrei Y. Kostritskii, Jan-Philipp Machtens
Summary: The study identified that the main ion-conductive state of TMEM16 lipid scramblases is modulated by lipid headgroups, and different scramblase isoforms regulate ion selectivity through their amino-acid composition.
NATURE COMMUNICATIONS
(2021)
Review
Biochemistry & Molecular Biology
Michel J. A. M. van Putten, Christoph Fahlke, Karl W. Kafitz, Jeannette Hofmeijer, Christine R. Rose
Summary: Ischemic stroke is a major cause of mortality and chronic disability, with astrocytes playing a central role in the dynamics of recovery or progression of stroke-induced brain damage. Dysfunction of astrocytes can lead to issues such as maintenance of cellular volume and cerebral edema under ischemic conditions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Neurosciences
Miriam Engels, Manu Kalia, Sarah Rahmati, Laura Petersilie, Peter Kovermann, Michel J. A. M. van Putten, Christine R. Rose, Hil G. E. Meijer, Thomas Gensch, Christoph Fahlke
Summary: The study found that astrocytes in different brain regions have different chloride ion concentrations and are regulated by different chloride ion transport proteins. Neocortical astrocytes with higher numbers of NKCC1 and KCC transporters have lower chloride ion concentrations. Chloride accumulation and efflux compensate for each other, preventing glial swelling under transient energy deprivation.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
Article
Clinical Neurology
Peter Kovermann, Yulia Kolobkova, Arne Franzen, Christoph Fahlke
Summary: Mutations in the gene SLC1A2 encoding the excitatory amino acid transporter 2 (EAAT2) are associated with severe forms of epileptic encephalopathy. Mutations G82R and L85P contribute to the formation of an anion pore in EAAT2, allowing glutamate efflux, while mutation P289R decreases glutamate uptake but increases anion currents, leading to glutamate excitotoxicity and neuronal hyperexcitability in affected patients. Therapeutic agents targeting the EAAT anion channel function could be beneficial in the future.
Review
Neurosciences
Peter Kovermann, Miriam Engels, Frank Mueller, Christoph Fahlke
Summary: Excitatory amino acid transporters (EAATs) play a crucial role in optimizing the temporal resolution and energy demand of excitatory synapses. In addition to their primary transport function, EAATs also function as anion channels. Recent research has shed light on the physiological and pathophysiological roles of EAAT anion channels.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Article
Biophysics
Andrei Y. Kostritskii, Jan -Philipp Machtens
Summary: The ability to sense transmembrane voltage and understand the molecular basis of voltage coupling in voltage-gated sodium channels is crucial for understanding their physiological roles. This study provides new insights into the voltage-sensing mechanisms of Nav channels through high-resolution quantification of VSD electrostatics, revealing the importance of electric-field reshaping for voltage sensing.
BIOPHYSICAL JOURNAL
(2023)
Article
Multidisciplinary Sciences
Bettina Kolen, Bart Borghans, Daniel Kortzak, Victor Lugo, Cora Hannack, Raul E. Guzman, Ghanim Ullah, Christoph Fahlke
Summary: In glutamatergic neurons, vesicular glutamate transporters act as H+/anion exchangers for selective glutamate accumulation in synaptic vesicles. This study reveals that VGLUT1 functions as H+-glutamate exchanger with variable transport coupling and as a Cl- efflux pathway through an aqueous anion channel. Mathematical modeling demonstrates that H+ coupling enables selective glutamate accumulation, while VGLUT1's Cl- channel function increases transport efficiency.
NATURE COMMUNICATIONS
(2023)
Meeting Abstract
Clinical Neurology
Daniela Stausberg, David Ewers, Friederike Arlt, Klaus-Armin Nave, Michael Sereda
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2022)
Meeting Abstract
Clinical Neurology
Doris Krauter, David Ewers, Timon J. Hartmannn, Theresa Kungl, Robert Fledrich, Sandra Goebbels, Klaus-Armin Nave, Michael W. Sereda
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2021)