Article
Biochemistry & Molecular Biology
Kamil Latka, Marek Bajda
Summary: This study reveals the binding mode of tiagabine in different states and compares them using molecular dynamics simulations and energy calculations. The results indicate that the binding mode of tiagabine in an outward-open state is more stable and favorable, consistent with previous molecular modeling findings. However, the binding position of tiagabine in an inward-open state is less stable and requires further experimental verification.
Article
Biochemistry & Molecular Biology
Angqi Zhu, Junhao Huang, Fang Kong, Jiaxin Tan, Jianlin Lei, Yafei Yuan, Chuangye Yan
Summary: Four cryogenic electron microscopy structures of GAT1 reveal the molecular mechanism and mode of action of two inhibitors.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Zenia Motiwala, Nanda Gowtham Aduri, Hamidreza Shaye, Gye Won Han, Jordy Homing Lam, Vsevolod Katritch, Vadim Cherezov, Cornelius Gati
Summary: In this study, the structure of GAT1 protein in complex with the drug tiagabine was determined using cryo-electron microscopy. The results reveal that tiagabine inhibits GAT1 by blocking the intracellular gate and suppressing neurotransmitter uptake. This study provides important insights into the biology and pharmacology of neurotransmitter transporters and offers a blueprint for the design of neuromodulators.
Article
Behavioral Sciences
Sum Yi Ma, Kin Ming Kwan
Summary: The study found that early prenatal exposure to VPA in mice led to tail deformation and decreased cerebellar weight and size, with reduced expression of GAD 65 and GAD 67 in the cerebellum of adult mice showing autistic behavior. Additionally, protein expressions of GAT-1 and GABAT were reduced in VPA mice, suggesting alterations in GABA production, recycling, and metabolism that could disrupt the excitatory-inhibitory balance in the autistic cerebellum.
BEHAVIOURAL BRAIN RESEARCH
(2022)
Review
Biochemistry & Molecular Biology
Ryuta Jomura, Shin-ichi Akanuma, Masanori Tachikawa, Ken-ichi Hosoya
Summary: This study focuses on the role of transporters that recognize Cr and/or Cr precursors in maintaining high energy levels in cells. The SLC6A and SLC16A family of transporters play important roles in the process of Cr biosynthesis and distribution via permeation of Cr and Cr precursors across the plasma membrane.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2022)
Review
Immunology
Yu Shan, Jianan Zhao, Yixin Zheng, Shicheng Guo, Steven J. Schrodi, Dongyi He
Summary: Rheumatoid arthritis (RA) is a disabling autoimmune disease with a complex pathological process. The GABAergic system in the nervous system may have immunomodulatory effects and regulate abnormal pain response in RA patients.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Radiology, Nuclear Medicine & Medical Imaging
Andrei Manzhurtsev, Alexey N. Yakovlev, Petr A. Bulanov, Petr E. Menshchikov, Maxim Ublinskiy, Ilya A. Melnikov, Tolib A. Akhadov, Natalia A. Semenova
Summary: Acute mTBI leads to an increase in GABA concentration in the posterior cingulate cortex (PCC) of pediatric patients, potentially indicating activation of GABA synthesis and impairment of the GABAergic system after acute mTBI.
JOURNAL OF MAGNETIC RESONANCE IMAGING
(2023)
Article
Biochemistry & Molecular Biology
Kazuya Matsuo, Yasushi Yabuki, Ronald Melki, Luc Bousset, Yuji Owada, Kohji Fukunaga
Summary: The study demonstrates that injecting α-Syn fibrils into the dorsal striatum impairs cognition and leads to the accumulation of phosphorylated α-Syn and reduction of GABAergic neurons in the medial septum/diagonal band. Deletion of Fabp3 antagonizes the neurotoxicity of α-Syn and cognitive impairment, suggesting that FABP3 could be a therapeutic target for dementia in synucleinopathies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biology
Yoshifumi Takahata, Hiromasa Hagino, Ayaka Kimura, Mitsuki Urushizaki, Sachi Kobayashi, Kanta Wakamori, Chika Fujiwara, Eriko Nakamura, Kayon Yu, Hiroshi Kiyonari, Kana Bando, Tomohiko Murakami, Toshihisa Komori, Kenji Hata, Riko Nishimura
Summary: Scientists identify Smoc1 and Smoc2 as novel targets for Runx2, playing important roles in bone formation. Double knockout mice for Smoc1 and Smoc2 show skeletal developmental abnormalities, indicating their involvement in intramembranous and endochondral bone formation. Their findings may lead to novel therapeutic strategies for various bone and cartilage diseases.
COMMUNICATIONS BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Florian P. Fischer, Ameya S. Kasture, Thomas Hummel, Sonja Sucic
Summary: This article introduces human gamma-aminobutyric acid transporter 1 (hGAT-1) and its role in the central nervous system as well as the disease-related mutations. Additionally, it discusses the methods for correcting protein folding defects and highlights the significance of using fruit flies as a research model.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Agriculture, Multidisciplinary
Benjie Li, Ying Yan, Guangkai Yao, Ling Zhang, Fei Lin, Hanhong Xu
Summary: A series of novel pyrazoloquinazolines were synthesized, and pyrazoloquinazoline 5a was found to have high insecticidal activity against the diamondback moth without cross-resistance to fipronil. Electrophysiological experiments suggested that 5a acts on the GABAR and GluCl. The potency of 5a on PxGluCl was 15-fold higher than fipronil, explaining the lack of cross-resistance. Downregulation of PxGluCl transcription significantly enhanced the insecticidal activity of 5a on the diamondback moth.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Magdalena Kowalska, Lukasz Fijalkowski, Alicja Nowaczyk
Summary: Studies have shown that neurogenesis in the brains of adult mammals is continuous, and that the antidepressant paroxetine may primarily exert its neurogenic effects through interactions with serotonin transporters.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Neurosciences
Ameya S. S. Kasture, Florian P. P. Fischer, Lisa Kunert, Melanie L. L. Burger, Alexander C. C. Burgstaller, Ali El-Kasaby, Thomas Hummel, Sonja Sucic
Summary: Mutations in the hGAT-1 gene can cause various types of epilepsy and the molecular mechanism behind these mutations has been investigated. Additionally, potential therapeutic approaches have been identified.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Deepthi Joseph, Smruti Ranjan Nayak, Aravind Penmatsa
Summary: This study investigates the structure and activity of GAT1 by modifying the dopamine transporter in Drosophila melanogaster. The findings suggest that the binding site undergoes substantial changes in order to accommodate GAT1 inhibitors, and an additional allosteric site is observed in the extracellular vestibule. The study also suggests a role for a specific motif in the selective control of neurotransmitter uptake.
Article
Multidisciplinary Sciences
Giulia Romano, Nikola Holodkov, Raffaella Klima, Fabian Feiguin
Summary: Alterations in the function of the RNA-binding protein TDP-43 are closely associated with the pathogenesis of ALS, leading to motor neuron degeneration. Pharmacological treatments aimed at potentiating GABA neurotransmission can reverse locomotion deficiencies in TBPH-minus flies, revealing novel therapeutic strategies for ALS.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Felix P. Mayer, Marco Niello, Daniela Cintulova, Spyridon Sideromenos, Julian Maier, Yang Li, Simon Bulling, Oliver Kudlacek, Klaus Schicker, Hideki Iwamoto, Fei Deng, Jinxia Wan, Marion Holy, Rania Katamish, Walter Sandtner, Yulong Li, Daniela D. Pollak, Randy D. Blakely, Marko D. Mihovilovic, Michael H. Baumann, Harald H. Sitte
Summary: Increasing extracellular levels of serotonin can ameliorate symptoms of depression and anxiety-related disorders. The study found that certain ring-substituted cathinones show preference for the release of serotonin and exert 5-HT-associated effects in behavioral models. These compounds have low abuse liability and potential for adverse events.
MOLECULAR PSYCHIATRY
(2023)
Article
Biochemistry & Molecular Biology
Matthew Thakur, Alex Bateman, Cath Brooksbank, Mallory Freeberg, Melissa Harrison, Matthew Hartley, Thomas Keane, Gerard Kleywegt, Andrew Leach, Mariia Levchenko, Sarah Morgan, Ellen M. McDonagh, Sandra Orchard, Irene Papatheodorou, Sameer Velankar, Juan Antonio Vizcaino, Rick Witham, Barbara Zdrazil, Johanna McEntyre
Summary: EMBL-EBI is one of the world's leading sources of public biomolecular data, offering sustainable, high-quality data that can serve as training sets for deep learning and artificial intelligence applications. The open availability of their extensive curated databases makes them ideal for research in the life sciences.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Marco Niello, Spyridon Sideromenos, Ralph Gradisch, Ronan O'Shea, Jakob Schwazer, Julian Maier, Nina Kastner, Walter Sandtner, Kathrin Jantsch, Carl R. Lupica, Alexander F. Hoffman, Gert Lubec, Claus J. Loland, Thomas Stockner, Daniela D. Pollak, Michael H. Baumann, Harald H. Sitte
Summary: By using various in vitro, computational, and in vivo approaches, we found that the drug-binding kinetics of S-enantiomers of pyrovalerone analogs at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, the slow dissociation (i.e., slow koff) of S-enantiomers of pyrovalerone analogs from DAT can predict their more persistent in vivo effects compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT in determining the in vivo profile of effects produced by psychostimulant drugs.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Editorial Material
Chemistry, Multidisciplinary
Rajarshi Guha, Barbara Zdrazil, Nina Jeliazkova, Karina Martinez-Mayorga
JOURNAL OF CHEMINFORMATICS
(2023)
Editorial Material
Psychiatry
Felix P. Mayer, Dino Luethi, Lorena B. Areal, Harald H. Sitte
FRONTIERS IN PSYCHIATRY
(2023)
Article
Cell Biology
Thomas J. F. Angenoorth, Julian Maier, Stevan Stankovic, Shreyas Bhat, Sonja Sucic, Michael Freissmuth, Harald H. Sitte, Jae-Won Yang
Summary: Organic cation transporters (OCTs) are membrane proteins that uptake monoamines, cationic drugs and xenobiotics. In this study, the researchers investigated two potentially misfolded variants of organic cation transporter 3 (OCT3) and found that pre-treatment with the chemical chaperone 4-PBA led to increased membrane expression and transport capacity of the misfolded variants. This study provides proof of principle that folding-deficient SLC22 transporter variants, especially OCT3, can be rescued by chaperones.
Editorial Material
Chemistry, Multidisciplinary
Eva Nittinger, Alex Clark, Anna Gaulton, Barbara Zdrazil
JOURNAL OF CHEMINFORMATICS
(2023)
Article
Medicine, General & Internal
Michael Eigenschink, Luise Bellach, Sebastian Leonard, Tom Eric Dablander, Julian Maier, Fabian Dablander, Harald H. Sitte
Summary: This study investigates the popularity, usage, and perceived scientific support of Traditional Chinese Medicine (TCM) in Austria. It found that TCM is widely known and used by a substantial proportion of the population, but there is a disparity between the public perception of TCM as scientific and evidence-based studies. It emphasizes the importance of distributing unbiased, science-driven information.
Article
Biology
Zsuzsanna Gyongy, Gabor Mocsar, Eva Hegedus, Thomas Stockner, Zsuzsanna Ritter, Laszlo Homolya, Anita Schamberger, Tamas Orban, Judit Remenyik, Gergely Szakacs, Katalin Goda
Summary: This study presents methods for simultaneously investigating substrate and nucleotide binding by ABCG2 in cells. The switch from the inward-facing to the outward-facing conformation of ABCG2 is induced by nucleotide binding and facilitated by substrates, while hindered by the inhibitor Ko143. The high-to-low affinity switch of the drug binding site coincides with the transition from the inward-facing to the outward-facing conformation.
Article
Psychiatry
Jacqueline D. Keighron, Jordi Bonaventura, Yang Li, Jae-Won Yang, Emily M. M. DeMarco, Melinda Hersey, Jianjing Cao, Walter Sandtner, Michael Michaelides, Harald H. H. Sitte, Amy Hauck Newman, Gianluigi Tanda
Summary: Typical and atypical dopamine uptake inhibitors (DUIs) have different effects on behavior, neurochemistry, and addiction potential due to their preference for distinct conformations of the dopamine transporter (DAT) to form ligand-transporter complexes. Cocaine and typical psychostimulants reduce dopamine clearance rate, but only typical DUIs stimulate evoked dopamine release, unrelated to DAT affinity. Pretreatment with a CaMKII alpha inhibitor blunts the stimulatory effects of cocaine on dopamine release, suggesting a role for this kinase in modulating cocaine's effects. Atypical DUIs blunt cocaine's effects, indicating a unique mechanism underlying their potential as medications for psychostimulant use disorder.
TRANSLATIONAL PSYCHIATRY
(2023)
Review
Physiology
Manan Bhatt, Laure Gauthier-Manuel, Erika Lazzarin, Rocco Zerlotti, Christine Ziegler, Andre Bazzone, Thomas Stockner, Elena Bossi
Summary: γ-Aminobutyric acid (GABA) acts as the primary inhibitory neurotransmitter in the CNS, regulated by GABA transporters (GATs). Although GAT1 has been extensively studied, the roles of other GABA transporters, especially BGT-1, remain unclear. This review aims to compare GAT1 and BGT-1, leveraging the knowledge of GAT1 to shed light on the unanswered questions regarding BGT-1.
FRONTIERS IN PHYSIOLOGY
(2023)
Article
Chemistry, Medicinal
Kornel Ozvoldik, Thomas Stockner, Elmar Krieger
Summary: The transition from 3D glasses to VR headsets in the industry has brought challenges for modelers. However, a novel software implementation using a VR headset at a desk has been introduced, providing a relaxing and immersive workplace. This software, called YASARA Model, combines VR functionality with a molecular graphics engine and offers additional features and interactive tutorials.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Review
Biotechnology & Applied Microbiology
Michael W. Mullowney, Katherine R. Duncan, Somayah S. Elsayed, Neha Garg, Justin J. J. van der Hooft, Nathaniel I. Martin, David Meijer, Barbara R. Terlouw, Friederike Biermann, Kai Blin, Janani Durairaj, Marina Gorostiola Gonzalez, Eric J. N. Helfrich, Florian Huber, Stefan Leopold-Messer, Kohulan Rajan, Tristan de Rond, Jeffrey A. van Santen, Maria Sorokina, Marcy J. Balunas, Mehdi A. Beniddir, Doris A. van Bergeijk, Laura M. Carroll, Chase M. Clark, Djork-Arne Clevert, Chris A. Dejong, Chao Du, Scarlet Ferrinho, Francesca Grisoni, Albert Hofstetter, Willem Jespers, Olga V. Kalinina, Satria A. Kautsar, Hyunwoo Kim, Tiago F. Leao, Joleen Masschelein, Evan R. Rees, Raphael Reher, Daniel Reker, Philippe Schwaller, Marwin Segler, Michael A. Skinnider, Allison S. Walker, Egon L. Willighagen, Barbara Zdrazil, Nadine Ziemert, Rebecca J. M. Goss, Pierre Guyomard, Andrea Volkamer, William H. Gerwick, Hyun Uk Kim, Rolf Mueller, Gilles P. van Wezel, Gerard J. P. van Westen, Anna K. H. Hirsch, Roger G. Linington, Serina L. Robinson, Marnix H. Medema
Summary: The developments in computational omics technologies in combination with artificial intelligence approaches have opened up new possibilities for drug discovery. However, addressing key challenges such as high-quality datasets and algorithm validation is essential to realize the potential of these synergies.
NATURE REVIEWS DRUG DISCOVERY
(2023)
Article
Biochemistry & Molecular Biology
Barbara Zdrazil, Eloy Felix, Fiona Hunter, Emma J. Manners, James Blackshaw, Sybilla Corbett, Marleen de Veij, Harris Ioannidis, David Mendez Lopez, Juan F. Mosquera, Maria Paula Magarinos, Nicolas Bosc, Ricardo Arcila, Tevfik Kiziloren, Anna Gaulton, A. Patricia Bento, Melissa F. Adasme, Peter Monecke, Gregory A. Landrum, Andrew R. Leach
Summary: ChEMBL is a curated resource of bioactive molecules with drug-like properties. It has evolved significantly in size and diversity of data types over time. The inclusion of new datasets has expanded the bioactivity data available and added new features to ChEMBL.
NUCLEIC ACIDS RESEARCH
(2023)
