Article
Neurosciences
Kiran Sapkota, Erica S. Burnell, Mark W. Irvine, Guangyu Fang, Dinesh Y. Gawande, Shashank M. Dravid, David E. Jane, Daniel T. Monaghan
Summary: The study characterizes a novel NMDAR antagonist, UBP792, which displays partial subtype-selectivity and inhibits NMDAR responses by reducing the potency and efficacy of L-glutamate and glycine. It acts non-competitively, with activity independent of voltage and affected by pH, and potentially stabilizes different channel conformations to inhibit NMDAR function. This expands the possibilities for developing NMDAR modulators with appropriate selectivity for therapeutic indications.
Article
Biochemistry & Molecular Biology
Allison L. Germann, Ariel B. Burbridge, Spencer R. Pierce, Gustav Akk
Summary: GABA(A) receptors play an important role in inhibitory neurotransmission in the brain. In this study, the functional properties of the rat alpha 1 beta 2 epsilon GABA(A) receptor were characterized. It was found that this receptor exhibits higher constitutive activity and reduced response to certain drugs. Surprisingly, amino acid substitutions in the epsilon subunit did not produce expected functional effects.
Article
Cell Biology
Shanti Pal Gangwar, Laura Y. Yen, Maria V. Yelshanskaya, Alexander I. Sobolevsky
Summary: In this study, cryo-EM structures of KAR GluK2 in complex with positive allosteric modulator BPAM344, competitive antagonist DNQX, and negative allosteric modulator perampanel were presented. The structures revealed the binding of two BPAM344 molecules per ligand-binding domain dimer interface. In the absence of an agonist or in the presence of DNQX, BPAM344 stabilized GluK2 in the closed state. The closed state was also stabilized by perampanel, which bound to the ion channel extracellular collar sites located in two out of four GluK2 subunits. These findings provide insights into the molecular mechanisms of positive and negative allosteric modulation of KARs.
Article
Neurosciences
Sakiko Taniguchi, Jacob R. Stolz, Geoffrey T. Swanson
Summary: Perampanel (PMP) has been found to inhibit both AMPAR and KARs, suggesting that its clinical actions may arise from selective inhibition of different glutamate receptor signaling pathways.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Biology
Lei Liu, Zhiran Fan, Xavier Rovira, Li Xue, Salome Roux, Isabelle Brabet, Mingxia Xin, Jean-Philippe Pin, Philippe Rondard, Jianfeng Liu
Summary: G protein-coupled receptors (GPCRs) form homo- and heterodimers with allosteric cross-talk that fine-tunes transmembrane signaling. Investigating the action of positive allosteric modulators (PAMs) at the transmembrane interface of GABA(B) receptor revealed their specific modulation of GPCR dimers. The study showed that PAMs act at the active interface between transmembrane domains, impacting the function of GPCR dimers.
Review
Pharmacology & Pharmacy
Casey Gallagher, Damien A. Ha, Robert J. Harvey, Robert J. Vandenberg
Summary: Glycine receptors are ligand-gated ion channels that mediate synaptic inhibition in the central nervous system, and they have emerged as promising targets for pain therapies. Despite advances in determining the high-resolution structures of these receptors, the development of potent and selective modulators that lack side effects remains challenging.
PHARMACOLOGICAL REVIEWS
(2022)
Article
Multidisciplinary Sciences
Shivani Choudhary, Melanie Abongwa, Sudhanva S. Kashyap, Saurabh Verma, Gunnar R. Mair, Daniel Kulke, Richard J. Martin, Alan P. Robertson
Summary: In this study, a GluCls subunit from Brugia malayi was cloned and its pharmacological properties were investigated. The results showed that the receptor was regulated by the natural ligand L-glutamate and ivermectin, and had dual effects when exposed to nodulisporic acid. Furthermore, the unique pharmacological characteristics of this GluCls subunit could explain the variation in drug sensitivities observed in different nematode parasites.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Neurosciences
Ruth C. Werthmann, Manuel Tzouros, Jens Lamerz, Angelique Augustin, Thorsten Fritzius, Luca Trovo, Michal Stawarski, Adi Raveh, Catherine Diener, Christophe Fischer, Martin Gassmann, Lothar Lindemann, Bernhard Bettler
Summary: Recent studies have shown that mGlu1 and mGlu5 form functional heterodimers in the brain, exhibiting symmetric signal transduction where both protomers need to reach an active conformation for full receptor activity. This highlights differences in the signaling transduction of heterodimeric mGluRs that influence allosteric modulation.
Article
Biochemistry & Molecular Biology
Casey I. Gallagher, Zachary J. Frangos, Diba Sheipouri, Susan Shimmon, Meryem-Nur Duman, Srinivasan Jayakumar, Christopher L. Cioffi, Tristan Rawling, Robert J. Vandenberg
Summary: This study synthesized a series of N-acyl amino acids (NAAAs) that inhibit the glycine transporter GlyT2 and enhance glycine receptor GlyRs. NAAAs with a phenylene ring in the acyl tail showed the best efficacy, and those with a lysine headgroup exhibited the strongest inhibition of GlyT2. The optimal modulator, (2S)-6-amino-2-[8-(2-octylphenyl)octanoylamino]hexanoic acid (8-8OPLys), inhibits GlyT2 with an IC50 of 192 nM and potentiates GlyRs by up to 335% at 1 μM. In a dual GlyT2/GlyRα(1) expression system, 8-8 OPLys showed the greatest reduction in the EC50 for glycine, suggesting the potential for developing new non-opioid analgesics for chronic pain treatment.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Chemistry, Organic
Marvin Korff, Judith Lueken, Judith Schmidt, Dirk Schepmann, Gunnar Goerges, Nadine Ritter, Paul Disse, Julian A. Schreiber, Guiscard Seebohm, Bernhard Wuensch
Summary: The study synthesized novel antagonists of GluN2B subunit containing NMDA receptors through the reaction of aryloxiranes with benzylpiperidines. One derivative showed high affinity and inhibitory activity, while another derivative showed promising bioavailability.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Biology
Shuya Kate Huang, Omar Almurad, Reizel J. Pejana, Zachary A. Morrison, Aditya Pandey, Louis-Philippe Picard, Mark Nitz, Adnan Sljoka, R. Scott Prosser
Summary: Cholesterol indirectly modulates the conformational equilibria and signaling of the adenosine A(2A) receptor by influencing membrane properties.
Article
Multidisciplinary Sciences
Dawid Deneka, Sonja Rutz, Cedric A. J. Hutter, Markus A. Seeger, Marta Sawicka, Raimund Dutzler
Summary: In this study, nanobodies targeting the LRR domain of LRRC8A have been developed and characterized, providing specific modulators for LRRC8 proteins and revealing the role of their cytoplasmic domains in regulating channel activity through allosteric mechanisms. Cryo-electron microscopy and electrophysiology experiments showed that these nanobodies can alter LRRC8A channel activity by binding to distinct epitopes of the LRR domain and changing channel conformations.
NATURE COMMUNICATIONS
(2021)
Article
Endocrinology & Metabolism
Guichang Zou, Jing Xia, Heyi Luo, Dan Xiao, Jin Jin, Chenjian Miao, Xin Zuo, Qianqian Gao, Zhi Zhang, Tian Xue, Yezi You, Ye Zhang, Li Zhang, Wei Xiong
Summary: The combined use of cannabis and alcohol leads to greater psychoactive toxicity than using either substance alone, and the underlying mechanisms behind this worsened outcome are still unclear. This study reveals that the synergistic effect of THC and ethanol on motor incoordination in mice is achieved by activating CB1R and potentiating GlyR within cerebellar PCs. Ethanol enhances THC actions by increasing its permeability across the blood-brain barrier and enriching THC in the cell membrane.
Article
Neurosciences
Dolores Piniella, Francisco Zafra
Summary: This article discusses the functions of NMDA-type glutamate receptors (NMDARs) in the central nervous system and their interaction with other endogenous ligands. The activity of NMDARs depends on the coincidental binding of glutamate with other cellular signals and is modulated by allosteric modulators such as zinc and protons. The GlyT1 transporter plays an important role in maintaining glycine concentration in the microenvironment of NMDARs. Although the inhibition of GlyT1 has been investigated as a treatment for schizophrenia, the results from phase III clinical trials have been disappointing. However, further research and the newly published 3D structure of GlyT1 may lead to the design of more effective drugs.
Article
Neurosciences
Simon Bossi, Dhanasak Dhanasobhon, Graham C. R. Ellis-Davies, Jimena Frontera, Marcel de Brito Van Velze, Joana Lourenco, Alvaro Murillo, Rafael Lujan, Mariano Casado, Isabel Perez-Otano, Alberto Bacci, Daniela Popa, Pierre Paoletti, Nelson Rebola
Summary: This study investigates the role of GluN3A subunits in the brain and reveals that they control the excitability of cortical and amygdalar circuits through the formation of eGlyRs and their activation by extracellular glycine. These eGlyRs are important in specific neuronal populations in the amygdala and neocortex, and play a role in fear memory and cortical activity modulation.
Article
Multidisciplinary Sciences
Mei-Lin Shen, Chen-Hung Wang, Ching-Huei Lin, Ning Zhou, Shung-Te Kao, Dong Chuan Wu
SCIENTIFIC REPORTS
(2016)
Article
Multidisciplinary Sciences
Mei-Lin Shen, Chen-Hung Wang, Rita Yu-Tzu Chen, Ning Zhou, Shung-Te Kao, Dong Chuan Wu
SCIENTIFIC REPORTS
(2016)
Article
Multidisciplinary Sciences
Ching-Huei Lin, Shih-Pin Hsu, Ting-Chun Cheng, Chin-Wei Huang, Yao-Chang Chiang, I-Han Hsiao, Ming-Hsueh Lee, Mei-Lin Shen, Dong Chuan Wu, Ning Zhou
SCIENTIFIC REPORTS
(2017)
Article
Neurosciences
Chen-Hung Wang, Ciria C. Hernandez, Junyi Wu, Ning Zhou, Hsin-Yu Hsu, Mei-Lin Shen, Yi-Ching Wang, Robert L. Macdonald, Dong Chuan Wu
JOURNAL OF NEUROSCIENCE
(2018)
Article
Endocrinology & Metabolism
Ning Zhou, Ravi L. Rungta, Aqsa Malik, Huili Han, Dong Chuan Wu, Brian A. MacVicar
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
(2013)
Article
Biochemistry & Molecular Biology
Shu Yan Yu, Dong Chuan Wu, Lidong Liu, Yuan Ge, Yu Tian Wang
JOURNAL OF NEUROCHEMISTRY
(2008)
Article
Neurosciences
Ning Zhou, Chen-Hung Wang, Shu Zhang, Dong Chuan Wu
JOURNAL OF NEUROSCIENCE
(2013)
Article
Neurosciences
Paola Virginia Migues, Oliver Hardt, Dong Chuan Wu, Karine Gamache, Todd Charlton Sacktor, Yu Tian Wang, Karim Nader
NATURE NEUROSCIENCE
(2010)
Article
Neurosciences
Gemma L. Dalton, Dong Chuan Wu, Yu Tian Wang, Stan B. Floresco, Anthony G. Phillips
Article
Multidisciplinary Sciences
Ching-Huei Lin, Mei-Lin Shen, Ning Zhou, Chen-Chen Lee, Shung-Te Kao, Dong Chuan Wu
Article
Cell & Tissue Engineering
Shih-Ping Liu, Ru-Huei Fu, Dong-Chuan Wu, Chien-Yu Hsu, Cheng-Hsuan Chang, Wei Lee, Yu-Da Lee, Chia Hui Liu, Ying-Jiun Chien, Shinn-Zong Lin, Woei-Cherng Shyu
STEM CELLS AND DEVELOPMENT
(2014)
Article
Multidisciplinary Sciences
Yuan Ge, Meng Tian, Lidong Liu, Tak Pan Wong, Bo Gong, Dongchuan Wu, Taesup Cho, Shujun Lin, Jurgen Kast, Jie Lu, Yu Tian Wang
NATURE COMMUNICATIONS
(2019)
Article
Neurosciences
Yitao Liu, Tak Pan Wong, Michelle Aarts, Amanda Rooyakkers, Lidong Liu, Ted Weita Lai, Dong Chuan Wu, Jie Lu, Michael Tymianski, Ann Marie Craig, Yu Tian Wang
JOURNAL OF NEUROSCIENCE
(2007)
Article
Neurosciences
Dong Chuan Wu, Rita Yu-Tzu Chen, Ting-Chun Cheng, Yao-Chang Chiang, Mei-Lin Shen, Li-Ling Hsu, Ning Zhou