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
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.
Review
Pharmacology & Pharmacy
Anil Annamneedi, Caroline Gora, Ana Dudas, Xavier Leray, Veronique Bozon, Pascale Crepieux, Lucie P. Pellissier
Summary: Autism spectrum disorders (ASDs), characterized by deficits in social interaction and communication, and stereotyped behaviors, affect 1 in 100 children worldwide. G protein-coupled receptors (GPCRs), the largest family of cell-surface receptors, have been found to be genetically associated with ASD. Among the 23 GPCRs identified in the Simons Foundation Autism Research Initiative (SFARI) gene database, D2, 5-HT2A, CB1, OTR, and V1A show promising therapeutic potential for ASD.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Solveig G. Schmidt, Ulrik Gether, Claus J. Loland
Summary: Sodium-coupled neurotransmitter transporters are important in terminating synaptic neurotransmission, and research into their molecular transport mechanisms has been enlightening. Despite their structural differences, studies on neurotransmitter: sodium symporters and excitatory amino acid transporters are crucial in understanding their ion-dependence and transport kinetics. Single-molecule studies have been instrumental in expanding the understanding of protein-level transport across membranes.
NEUROCHEMICAL RESEARCH
(2022)
Article
Chemistry, Multidisciplinary
Stefanie Kickinger, Maria E. K. Lie, Akihiro Suemasa, Anas Al-Khawaja, Koichi Fujiwara, Mizuki Watanabe, Kristine S. Wilhelmsen, Christina B. Falk-Petersen, Bente Frolund, Satoshi Shuto, Gerhard F. Ecker, Petrine Wellendorph
Summary: This study designed and synthesized novel conformationally restricted cyclic GABA analogs, with bicyclo-GABA and its N-methylated analog identified as the most potent and selective BGT1 inhibitors. Pharmacological evaluation showed that these compounds are competitive inhibitors at BGT1, with bicyclo-GABA showing agonistic activity at GABA(A) receptors. Mutagenesis studies revealed the molecular determinants driving BGT1 activity and selectivity.
FRONTIERS IN CHEMISTRY
(2021)
Review
Cell Biology
Bradley M. Roberts, Emanuel F. Lopes, Stephanie J. Cragg
Summary: Striatal dopamine release is inhibited by striatal gamma-aminobutyric acid (GABA) acting via GABA(A) and GABA(B) receptors, which is regulated by plasma membrane GABA uptake transporters on striatal astrocytes. The regulation of striatal GABA-DA interactions serves as a potential therapeutic target for psychomotor disorders associated with dysregulated DA signaling.
Article
Biochemistry & Molecular Biology
Apostolos Mikroulis, Marco Ledri, Gabriele Ruffolo, Eleonora Palma, Guenther Sperk, Jesmond Dalli, Annamaria Vezzani, Merab Kokaia
Summary: Epilepsy is a severe neurological disease that affects about 1% of the population. Current drug treatments are ineffective for up to 40% of patients, highlighting the need for novel therapies. A molecule called PD1(n-3DPA) has been found to reduce seizures, cell loss, and cognitive deficits in a mouse model of epilepsy. Additionally, PD1(n-3DPA) may directly affect neuronal activity by modulating synaptic inputs.
Review
Endocrinology & Metabolism
Fanhua Wang, Mingyao Liu, Ning Wang, Jian Luo
Summary: This review discusses the role of G-protein coupled receptors (GPCRs) in osteoarthritis (OA), including the pathophysiological processes involved, preclinical and clinical trial data, and the challenges in developing therapies targeting GPCRs for OA.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Multidisciplinary Sciences
Zhen-Fei Chao, Ya-Ling Wang, Yuan-Yuan Chen, Chu-Ying Zhang, Peng-Yun Wang, Tao Song, Chu-Bin Liu, Qiao-Yan Lv, Mei-Ling Han, Shan-Shan Wang, Jianbing Yan, Ming-Guang Lei, Dai-Yin Chao
Summary: NAET1 and NAET2 are the NA transporters in plants responsible for the transport of iron and copper to seeds, predominantly expressed in shoot and root vascular tissues. They mediate the secretion of NA out of cells in a manner similar to the release of neurotransmitters from animal synaptic vesicles.
Article
Chemistry, Medicinal
Shengzhe Deng, Haiwei Zhang, Rongpei Gou, Ding Luo, Zerong Liu, Feng Zhu, Weiwei Xue
Summary: The study investigates the molecular mechanism underlying the transportation of human dopamine transporter (hDAT), which regulates the reuptake of extracellular dopamine (DA) and is an essential target for CNS diseases. Using a structure-based method, allosteric sites on hDAT in inward-open conformation were explored and compounds with allosteric affinity were screened. The discovery of a new allosteric inhibitor for hDAT provides a starting point for lead optimization and demonstrates the usability of the method for discovering novel allosteric modulators of other therapeutic targets.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Multidisciplinary
Stefanie Kampen, Duc Duy Vo, Xiaoqun Zhang, Nicolas Panel, Yunting Yang, Mariama Jaiteh, Pierre Matricon, Per Svenningsson, Jose Brea, Maria Isabel Loza, Jan Kihlberg, Jens Carlsson
Summary: This study presents a structure-based strategy to design compounds with dual-target properties, which can both antagonize the A(2A) adenosine receptor and activate the D-2 dopamine receptor, showing promising potential as anti-parkinson drugs.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Review
Plant Sciences
Mohammad Israil Ansari, Syed Uzma Jalil, Shamim Akhtar Ansari, Mirza Hasanuzzaman
Summary: Under unfavorable environmental conditions, plants produce high levels of ROS, causing oxidative damage to cells. However, plants have complex defense systems to scavenge ROS, with the GABA pathway playing a key role in this process.
PLANT GROWTH REGULATION
(2021)
Article
Neurosciences
Harrison J. Ramsay, Sara E. Gookin, Austin M. Ramsey, Dean J. Kareemo, Kevin C. Crosby, Dominik G. Stich, Samantha S. Olah, Hannah S. Actor-Engel, Katharine R. Smith, Matthew J. Kennedy
Summary: Postsynaptic neurotransmitter receptors and their associated scaffolding proteins form nanometer-scale subsynaptic domains (SSDs) within the postsynaptic membrane. The role of neurotransmitter signaling in the initial assembly of these SSDs during synapse development is still unknown.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2023)
Article
Biology
Ramon Cierco Jimenez, Nil Casajuana-Martin, Adrian Garcia-Recio, Lidia Alcantara, Leonardo Pardo, Mercedes Campillo, Angel Gonzalez
Summary: The study analyzed 119,069 natural variants in human olfactory receptors, revealing a significant diversity of natural variations in the olfactory gene repertoire between individuals and populations, with a considerable number of changes occurring at the structurally conserved regions. Mutations in positions linked to the conserved GPCR activation mechanism were highlighted, which could imply phenotypic variation in olfactory perception.
Review
Chemistry, Medicinal
Mohammed Akli Ayoub, Ranjit Vijayan
Summary: Hemorphins, short peptides derived from hemoglobin's beta subunit, have diverse physiological effects, particularly in the nervous and renin-angiotensin systems. They modulate a variety of proteins, including enzymes and receptors, and target G protein-coupled receptors (GPCRs) pharmacologically and functionally. The implication of GPCRs in hemorphins' effects aids in understanding their molecular basis and suggests the hemorphin-GPCR axis as a potential therapeutic target in various systems.
Article
Biochemical Research Methods
Johanna Irrgeher, Thomas Berger, Anastassiya Tchaikovsky, Cornelius Tschegg, Ghazaleh Gouya, Peter Lechner, Anika Retzmann, Christine Opper, Christa Firbas, Michael Freissmuth, Kerstin Peschel-Credner, Karolina Anderle, Claudia Meisslitzer, Michael Wolzt, Thomas Prohaska
Summary: This article presents an analysis method for Pb isotope pattern deconvolution using enriched Pb-204 as a tracer to monitor trace levels of Pb within the human body. The method overcomes the limitations of using natural lead as a tracer and allows for the calculation of isotope pattern from measured isotope ratios without knowing the quantities of different isotope sources.
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
(2023)
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
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
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.
Article
Biochemistry & Molecular Biology
Julika Radecke, Raphaela Seeger, Anna Kadkova, Ulrike Laugks, Amin Khosrozadeh, Kenneth N. Goldie, Vladan Lucic, Jakob B. Sorensen, Benoit Zuber
Summary: This study used cryo-electron tomography to observe the intermediate steps following synaptic stimulation, and found that during the early fusion stage after stimulation, synaptic vesicles undergo morphological changes to establish contact with the plasma membrane. The subsequent late fusion stage results in fusion pore opening and collapse of the synaptic vesicles. These morphological observations likely correspond to the transition of synaptic vesicles from one functional pool to another.
Article
Biochemistry & Molecular Biology
Michael Freissmuth
Summary: The level of dopamine transporters in the neuronal plasma membrane affects learning and motor coordination in mice. Kearney and colleagues recently showed that dopamine autoreceptors and metabotropic glutamate receptors control the cycling of dopamine transporters in the presynaptic specialization of dopaminergic neurons. These findings have important implications for future studies in neural development and motor learning.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Microbiology
Andrea Corona Ramirez, Kang Soo Lee, Adolfo Odriozola, Marek Kaminek, Roman Stocker, Benoit Zuber, Pilar Junier
Summary: The production of specialized resting cells is a survival strategy developed by organisms to withstand unfavorable environmental factors. Five bacterial taxa are recognized to form specialized resting cells, and they are characterized by low metabolic activity and higher resistance to environmental stress. A cross-species comparison of bacterial sporulation reveals a lack of common chemical signature among the specialized resting cells, with each group having a unique signature. The use of Raman spectroscopy enables the isolation of endospores based on their specific chemical signatures.
Article
Biochemistry & Molecular Biology
N. J. Clauss, F. P. Mayer, W. A. Owens, M. Vitela, K. M. Clarke, M. A. Bowman, R. E. Horton, D. Gruendemann, D. Schmid, M. Holy, G. G. Gould, W. Koek, H. H. Sitte, L. C. Daws
Summary: Concurrent cocaine and alcohol use is a dangerous drug combination that increases extracellular monoamines. Ethanol's ability to inhibit monoamine uptake is dependent on the organic cation transporter 3 (OCT3), while cocaine blocks DAT, NET, and SERT. These findings suggest OCT3 as a potential target for therapeutic intervention in ethanol and ethanol/cocaine use disorders.
MOLECULAR PSYCHIATRY
(2023)
Review
Cell Biology
Santosh Phuyal, Patrizia Romani, Sirio Dupont, Hesso Farhan
Summary: Mechanobiology is a field that investigates how cells sense and respond to physical forces, and the impact of these forces on organelles. Current knowledge on the mechanical properties of organelles and their response to external forces is limited, and further research is needed.
TRENDS IN CELL BIOLOGY
(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
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)
Article
Pharmacology & Pharmacy
Francesca R. Brugnoli, Marion Holy, Marco Niello, Julian Maier, Marcus Hanreich, Mario Menzel, Matthias Haberler, Niklas Zulus, Thomas Pickl, Christa Ivanova, Lisa D. Muiznieks, Benjamin Garlan, Harald H. Sitte
Summary: To address the drawbacks of current techniques in studying the interaction of monoamine transporters, researchers developed an automated microfluidic platform for more accurate and standardized cell-based assays. The platform successfully validated the effects of control compounds such as D-Amphetamine, GBR12909, p-chloroamphetamine, and paroxetine on the two transporters.
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
(2023)
Article
Chemistry, Organic
Jan Thiede, Simon Rothenbuhler, Ioan Iacovache, Simon M. Langenegger, Benoit Zuber, Robert Haner
Summary: This article presents the supramolecular self-assembly of pyrene-DNA conjugates into nanostructures. DNA functionalized with different types of pyrene isomers can self-assemble into nano-objects with various shapes. The research also constructs an artificial light-harvesting complex, which has implications for the design of photosynthetic devices.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Neurosciences
Felix P. Mayer, Marco Niello, Simon Bulling, Yuan-Wei Zhang, Yang Li, Oliver Kudlacek, Marion Holy, Fatemeh Kooti, Walter Sandtner, Gary Rudnick, Diethart Schmid, Harald H. Sitte
Summary: This study provides further insights into the pharmacology of mephedrone at hDAT and hSERT. It was found that mephedrone induces carrier-mediated release via hDAT and hSERT and is sensitive to protein kinase C inhibitor. Additionally, mephedrone displays greater efficacy as a releaser at hSERT than at hDAT, indicating its higher activity at hSERT.
Article
Biochemistry & Molecular Biology
Ankita Chadda, Alexander G. Kozlov, Binh Nguyen, Timothy M. Lohman, Eric A. Galburt
Summary: In this study, it was found that the DNA damage response in Mycobacterium tuberculosis differs from well-studied model bacteria. The DNA repair helicase UvrD1 in Mtb is activated through a redox-dependent process and is closely associated with the homo-dimeric Ku protein. Additionally, Ku protein is shown to stimulate the helicase activity of UvrD1.
JOURNAL OF MOLECULAR BIOLOGY
(2024)
