Article
Pharmacology & Pharmacy
Victoria R. Sanders, Neil S. Millar
Summary: Considerable progress has been made in the identification and characterization of subtype-selective modulators of nicotinic acetylcholine receptors (nAChRs), specifically alpha 7 nAChRs. This review focuses on alpha 7-selective modulators that bind to receptor sites other than the orthosteric agonist binding site for acetylcholine. The mechanism of action and binding sites of these modulators is still a topic of debate.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Sergey A. Vishnivetskiy, Elizabeth K. Huh, Preethi C. Karnam, Samantha Oviedo, Eugenia Gurevich, Vsevolod V. Gurevich
Summary: Arrestins preferentially bind phosphorylated G protein-coupled receptors (GPCRs) through their conserved middle loop, which directly interacts with the bound GPCR. Mutagenesis studies reveal that the middle loop primarily acts as a suppressor of binding to non-preferred forms of the receptor. Certain mutations in the middle loop enhance the binding to unphosphorylated light-activated rhodopsin, making them potential candidates for improving phosphorylation-independent arrestins. However, enhanced forms of arrestin do not bind GPCRs exactly like the wild-type protein, indicating the need for caution when interpreting the structures of arrestin-receptor complexes with different enhanced arrestin mutants and reengineered receptors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(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
Wessel A. C. Burger, Patrick R. Gentry, Alice E. Berizzi, Ziva Vuckovic, Emma T. van der Westhuizen, Geoff Thompson, Mahmuda Yeasmin, Craig W. Lindsley, Patrick M. Sexton, Christopher J. Langmead, Andrew B. Tobin, Arthur Christopoulos, Celine Valant, David M. Thal
Summary: The potential binding site for ML375 in M-5 mAChR was identified at the interface of TMs 2-4, aiding in the development of novel selective M-5 mAChR modulators.
ACS CHEMICAL NEUROSCIENCE
(2021)
Review
Biochemistry & Molecular Biology
Raudah Lazim, Donghyuk Suh, Jai Woo Lee, Thi Ngoc Lan Vu, Sanghee Yoon, Sun Choi
Summary: The presence of GPCR dimers has sparked research into their importance in disease pathogenesis and drug design, uncovering new signaling pathways and potential therapeutic targets. The increasing influence of computational methods in research is providing new avenues for understanding the functions and interactions of GPCRs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Physical
Fuhui Zhang, Yuan Yuan, Yichi Chen, Jianfang Chen, Yanzhi Guo, Xuemei Pu
Summary: This study investigates the allosteric mechanism of G protein-coupled receptors (GPCRs) in recruiting different transducers. The results show that the intracellular binding region of the receptor undergoes transducer-dependent changes, leading to differences in the activation of G-protein and beta-arrestin. The study also reveals specific interactions between the agonist and the receptor that are important for recruiting beta-arrestin. The findings provide valuable insights into biased activation mechanisms.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)
Article
Chemistry, Medicinal
Louise Dickson, Martin Teall, Elodie Chevalier, Toni Cheung, Gemma M. Liwicki, Stephen Mack, Anne Stephenson, Kathryn White, Richard Fosbeary, David C. Harrison, Nicola L. Brice, Kevin Doyle, Roberto Ciccocioppo, Chaobo Wu, Sarah Almond, Toshal R. Patel, Philip Mitchell, Matt Barnes, Andrew P. Ayscough, Lee A. Dawson, Mark Carlton, Roland W. Burli
Summary: In this study, highly potent and selective mGluR7 agonists, including CVN636, were identified, optimized, and characterized. CVN636 demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder, suggesting its potential as a drug candidate in CNS disorders involving mGluR7 and glutamatergic dysfunction.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Medicinal
Louise Dickson, Martin Teall, Elodie Chevalier, Toni Cheung, Gemma M. Liwicki, Stephen Mack, Anne Stephenson, Kathryn White, Richard Fosbeary, David C. Harrison, Nicola L. Brice, Kevin Doyle, Roberto Ciccocioppo, Chaobo Wu, Sarah Almond, Toshal R. Patel, Philip Mitchell, Matt Barnes, Andrew P. Ayscough, Lee A. Dawson, Mark Carlton, Roland W. Burli
Summary: In this study, highly potent and selective agonists for the low affinity metabotropic glutamate receptor mGluR7 were identified, optimized, and characterized. The chromane CVN636, in particular, showed exceptional selectivity for mGluR7 and demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder. As such, CVN636 has the potential to be a drug candidate for CNS disorders involving mGluR7 and glutamatergic dysfunction.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Immunology
Tehila Mizrachi, Oshrit Marsha, Karen Brusin, Yael Ben-David, Ganesh A. Thakur, Adi Vaknin-Dembinsky, Millet Treinin, Talma Brenner
Summary: GAT107, an ago-PAM of alpha 7 nAChR, can significantly reduce disease severity and neuroinflammation in EAE by activating the receptor, leading to decreased pro-inflammatory cytokine production and increased anti-inflammatory cytokine IL-10. It also alters the expression of immune cell markers and directly activates alpha 7 nAChR in immune cells of MS patients and healthy donors.
JOURNAL OF NEUROINFLAMMATION
(2021)
Article
Multidisciplinary Sciences
Geng Chen, Jun Xu, Asuka Inoue, Maximilian F. Schmidt, Chen Bai, Qiuyuan Lu, Peter Gmeiner, Zheng Liu, Yang Du
Summary: This study reports two structures of the human GPR88-Gi complex, revealing an allosteric ligand involved in the interaction between the receptor and G-protein, and a potential endogenous ligand of GPR88.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Miriam Scarpa, Colin Molloy, Laura Jenkins, Bethany Strellis, Rebecca F. Budgett, Sarah Hesse, Louis Dwomoh, Sara Marsango, Gonzalo S. Tejeda, Mario Rossi, Zeshan Ahmed, Graeme Milligan, Brian D. Hudson, Andrew B. Tobin, Sophie J. Bradley
Summary: Current treatments for neurodegenerative diseases like Alzheimer's disease have shown limited effectiveness, but activating the M1 receptor could potentially restore memory and slow disease progression. Recent research suggests that minimizing adverse reactions associated with M1 receptor activation can be achieved by ensuring proper phosphorylation and arrestin-dependent signaling. This approach shows promise for developing next-generation M1 receptor ligands with reduced side effects and improved neuroprotection.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Neurosciences
Jamie J. Manning, Hayley M. Green, Michelle Glass, David B. Finlay
Summary: The CB1 receptor is a promising drug target for a wide range of diseases, but existing ligands have limited therapeutic potential. Recent drug development efforts have focused on altering CB1 signaling by modulating endocannabinoid signaling or selectively targeting specific cellular pathways.
Article
Multidisciplinary Sciences
Fan Yang, Shenglong Ling, Yingxin Zhou, Yanan Zhang, Pei Lv, Sanling Liu, Wei Fang, Wenjing Sun, Liaoyuan A. Hu, Longhua Zhang, Pan Shi, Changlin Tian
Summary: Using single-particle cryo-electron microscopy, the structures of beta(2)AR-G alpha(s)beta gamma in complex with partial agonist salbutamol or full agonist isoprenaline were determined, revealing differences in binding affinity, hydrogen bonding interactions, hydrophobic interactions, and conformational changes between the two agonists. Stronger interactions between intracellular loop 2 or 3 (ICL2 or ICL3) of beta(2)AR and G alpha(s) observed in the salbutamol complex indicate potential mechanisms for decreased phosphorylation and beta(2)AR desensitization.
NATIONAL SCIENCE REVIEW
(2021)
Article
Pharmacology & Pharmacy
Hao Zhang, Guojun Chu, Gaoming Wang, Min Yao, Shaoyong Lu, Ting Chen
Summary: In this study, extensive molecular dynamics simulations were performed to investigate the conformational changes of the GPR97-G(o) complex in the presence or absence of G(o) palmitoylation. Structural and energetic analyses revealed that palmitoylation of G(o) stabilizes the active conformation of GPR97 and enhances ligand binding affinity. Community network analysis indicated that G(o) palmitoylation strengthens the interactions between G(alpha o) and G(beta gamma) and enhances the coupling between G(o) and GPR97. These findings provide mechanistic insights into the regulation of aGPCRs and have implications for future drug design targeting aGPCRs.
Article
Pharmacology & Pharmacy
Elita Yuliantie, Wijnand J. C. van der Velden, Viktorija Labroska, Antao Dai, Fenghui Zhao, Sanaz Darbalaei, Giuseppe Deganutti, Tongyang Xu, Qingtong Zhou, Dehua Yang, Mette M. Rosenkilde, Patrick M. Sexton, Ming-Wei Wang, Denise Wootten
Summary: This study investigated the structure-function relationship of GIPR, revealing two critical interaction networks that affect cAMP accumulation and recruitment of beta-arrestin 2. The activation of ERK1/2 was found to be largely independent of other signaling pathways, indicating distinct signaling properties.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Multidisciplinary Sciences
Simone Proemel, Franziska Fiedler, Claudia Binder, Jana Winkler, Torsten Schoeneberg, Doreen Thor
SCIENTIFIC REPORTS
(2016)
Article
Biotechnology & Applied Microbiology
Doreen Thor, Diana Le Duc, Rainer Strotmann, Torsten Schoeneberg
Article
Biochemistry & Molecular Biology
Maxi Coester, Doreen Wittkopf, Annika Kreuchwig, Gunnar Kleinau, Doreen Thor, Gerd Krause, Torsten Schoeneberg
Article
Biochemistry & Molecular Biology
Jianxin Hu, Doreen Thor, Yaru Zhou, Tong Liu, Yan Wang, Sara M. McMillin, Rajendra Mistry, R. A. John Challiss, Stefano Costanzi, Juergen Wess
Article
Biochemistry & Molecular Biology
Ines Liebscher, Uwe Mueller, Daniel Teupser, Eva Engemaier, Kathrin M. Y. Engel, Lars Ritscher, Doreen Thor, Katrin Sangkuhl, Albert Ricken, Antje Wurm, Daniel Piehler, Sandra Schmutzler, Herbert Fuhrmann, Frank W. Albert, Andreas Reichenbach, Joachim Thiery, Torsten Schoeneberg, Angela Schulz
JOURNAL OF BIOLOGICAL CHEMISTRY
(2011)
Article
Cell Biology
Juliane Roethe, Doreen Thor, Jana Winkler, Alexander B. Knierim, Claudia Binder, Sandra Huth, Robert Kraft, Sven Rothemund, Torsten Schoeneberg, Simone Proemel
Editorial Material
Multidisciplinary Sciences
Rory K. Morgan, Garret R. Anderson, Demet Arac, Gabriela Aust, Nariman Balenga, Antony Boucard, James P. Bridges, Felix B. Engel, Caroline J. Formstone, Maike D. Glitsch, Ryan S. Gray, Randy A. Hall, Cheng-Chih Hsiao, Hee-Yong Kim, Alexander B. Knierim, Deva Krupakar Kusuluri, Katherine Leon, Ines Liebscher, Xianhua Piao, Simone Proemel, Nicole Scholz, Swati Srivastava, Doreen Thor, Kimberley F. Tolias, Yuri A. Ushkaryov, Mario Vallon, Erwin G. Van Meir, Benoit Vanhollebeke, Uwe Wolfrum, Kevin M. Wright, Kelly R. Monk, Amit Mogha
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2019)
Article
Multidisciplinary Sciences
Alexander Bernd Knierim, Juliane Roethe, Mehmet Volkan Cakir, Vera Lede, Caroline Wilde, Ines Liebscher, Doreen Thor, Torsten Schoeneberg
SCIENTIFIC REPORTS
(2019)
Article
Biochemical Research Methods
Juliane Roethe, Robert Kraft, Torsten Schoeneberg, Doreen Thor
BIOLOGICAL PROCEDURES ONLINE
(2020)
Article
Endocrinology & Metabolism
Tomas Suchy, Christian Zieschang, Yulia Popkova, Isabell Kaczmarek, Juliane Weiner, Aenne-Dorothea Liebing, Mehmet Volkan cakir, Kathrin Landgraf, Martin Gericke, John Andrew Pospisilik, Antje Koerner, John T. Heiker, Dirk Dannenberger, Juergen Schiller, Torsten Schoeneberg, Ines Liebscher, Doreen Thor
INTERNATIONAL JOURNAL OF OBESITY
(2020)
Review
Biochemistry & Molecular Biology
Isabell Kaczmarek, Tomas Suchy, Simone Proemel, Torsten Schoeneberg, Ines Liebscher, Doreen Thor
Summary: Adhesion GPCRs (aGPCRs) are a unique class of orphan receptors with potential therapeutic targets. They can couple with G proteins and potentially expand the ways of influencing physiological functions. Besides their significance in the immune and central nervous systems, aGPCRs also play important roles in metabolic tissues.
BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Anastasia Georgiadi, Valeria Lopez-Salazar, Rabih El-Merahbi, Rhoda Anane Karikari, Xiaochuan Ma, Andre Mourao, Katarina Klepac, Lea Buhler, Ana Jimena Alfaro, Isabell Kaczmarek, Adam Linford, Madeleen Bosma, Olga Shilkova, Olli Ritvos, Nobuhiro Nakamura, Shigehisa Hirose, Maximilian Lassi, Raffaele Teperino, Juliano Machado, Marcel Scheideler, Arne Dietrich, Arie Geerlof, Annette Feuchtinger, Andreas Blutke, Katrin Fischer, Timo Dirk Muller, Katharina Kessler, Torsten Schoneberg, Doreen Thor, Silke Hornemann, Michael Kruse, Peter Nawroth, Olga Pivovarova-Ramich, Andreas Friedrich Hermann Pfeiffer, Michael Sattler, Matthias Bluher, Stephan Herzig
Summary: The FNDC4-GPR116, liver-white adipose tissue endocrine axis plays a crucial role in controlling glucose homeostasis, while disruption of sFNDC4-GPR116 axis is associated with severe metabolic dysfunction in obesity and diabetes. Furthermore, sFNDC4 promotes insulin signaling and glucose uptake in white adipocytes through direct binding to GPR116, leading to improved glucose tolerance and reduced inflammation in prediabetic mice.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Doreen Thor
Summary: This article discusses the expression profile of G protein-coupled receptors (GPCRs) and the impact of GPCR signaling on normal islet functionality.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2022)
Article
Endocrinology & Metabolism
Tomas Suchy, Isabell Kaczmarek, Tomislav Maricic, Christian Zieschang, Torsten Schoeneberg, Doreen Thor, Ines Liebscher
Summary: Cell lines can act as alternatives to animal or human studies, with the 3T3-L1 cell line being used to mimic adipocyte function. Generation of gene knock-outs using CRISPR/Cas approach in 3T3-L1 cells revealed unresponsiveness to isoprenaline in terms of adiponectin secretion and lipolysis.
Review
Pharmacology & Pharmacy
Kenneth A. Jacobson, Esmerilda G. Delicado, Christian Gachet, Charles Kennedy, Ivar von Kuegelgen, Beibei Li, M. Teresa Miras-Portugal, Ivana Novak, Torsten Schoeneberg, Raquel Perez-Sen, Doreen Thor, Beili Wu, Zhenlin Yang, Christa E. Mueller
BRITISH JOURNAL OF PHARMACOLOGY
(2020)