Article
Biochemistry & Molecular Biology
Kirsten L. Mcmahon, Henrik O'Brien, Christina I. Schroeder, Jennifer R. Deuis, Dhananjeyan Venkatachalam, Di Huang, Brad R. Green, Pradip K. Bandyopadhyay, Qing Li, Mark Yandell, Helena Safavi-Hemami, Baldomero M. Olivera, Irina Vetter, Samuel D. Robinson
Summary: This study identified new mu-conotoxins from species of the subgenera Textilia and Afonsoconus and investigated their selectivity at human Na-V channels using RNA-seq and DNA analysis techniques.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Review
Chemistry, Medicinal
James R. Groome
Summary: This article reviews the study of marine toxins, particularly on their actions on sodium ion channels regulated by transmembrane voltage and neurotransmitters. The focus is on the diverse conotoxin peptides and their potential applications in evolutionary relationships, biological actions, disease therapy, and understanding the structure of ion channels at the atomic level.
Article
Biochemistry & Molecular Biology
Altin Sula, David Hollingworth, Leo C. T. Ng, Megan Larmore, Paul G. DeCaen, B. A. Wallace
Summary: This study identified a previously unidentified receptor site within the NavMs voltage-gated sodium channel, where tamoxifen and its metabolic products bind, inhibiting sodium conductance and potentially leading to the development of new drugs for sodium channelopathies.
Review
Pharmacology & Pharmacy
Phuong T. Nguyen, Vladimir Yarov-Yarovoy
Summary: This review focuses on recent progress, current challenges, and future opportunities in developing sodium channel targeting small molecules and peptides as non-addictive therapeutics for treating pain.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Xin Wu, Liang Hong
Summary: Calmodulin (CaM) is a small protein that serves as a ubiquitous signal transducer, regulating neuronal plasticity, muscle contraction, and immune response. It interacts with ion channels and plays regulatory roles in cellular electrophysiology. Mutations in CaM-binding IQ domain can lead to various diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Pharmacology & Pharmacy
Jennifer R. Deuis, Lotten Ragnarsson, Samuel D. Robinson, Zoltan Dekan, Lerena Chan, Ai-Hua Jin, Poanna Tran, Kirsten L. McMahon, Shengnan Li, John N. Wood, James J. Cox, Glenn F. King, Volker Herzig, Irina Vetter
Summary: A peptide named β-theraphotoxin-Eo1a was discovered from the venom of the Tanzanian black and olive baboon tarantula, which modulates the function of Na(V)1.8 channels. Eo1a increases the peak current of Na(V)1.8 and causes significant shifts in the voltage-dependence of activation and steady-state fast inactivation.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Physiology
Jamie S. S. Lindner, Salil R. R. Rajayer, Briana J. J. Martiszus, Stephen M. M. Smith
Summary: The calcium-sensing receptor agonist, cinacalcet, regulates neuronal excitability by modulating the voltage-dependence of voltage-gated sodium channel (VGSC) currents. This regulation is achieved by shifting the voltage-dependence of VGSC currents and involves an unidentified inhibitory molecule that is G-protein dependent.
FRONTIERS IN PHYSIOLOGY
(2022)
Article
Multidisciplinary Sciences
Yichen Liu, Carlos A. Z. Bassetto, Bernardo I. Pinto, Francisco Bezanilla
Summary: In this study, authors have reinterpreted the mechanism of fast inactivation in eukaryotic Na+ channels based on structural analysis and current measurements. They found that the final inactivation gate in Nav1.4 channel is comprised of two hydrophobic rings that close downstream of IFM binding. This alternative molecular framework provides a new understanding of fast inactivation.
NATURE COMMUNICATIONS
(2023)
Review
Pharmacology & Pharmacy
Daohua Jiang, Jiangtao Zhang, Zhanyi Xia
Summary: Voltage-gated sodium channels are crucial for the rapid rising-phase of action potentials, and their mutations can lead to various human diseases. Recent studies using cryo-EM structures have provided valuable insights into the mechanism of eukaryotic Na-V channels, offering templates for drug development.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Nace Zidar, Tihomir Tomasic, Danijel Kikelj, Martina Durcik, Jan Tytgat, Steve Peigneur, Marc Rogers, Alexander Haworth, Robert W. Kirby
Summary: Voltage-gated sodium channels (Navs) play a crucial role in neurotransmission and their dysfunction is associated with various neurological disorders. In this study, a new series of aryl and acylsulfonamides were discovered as state-dependent inhibitors of Nav1.3 channels. These compounds displayed strong selective activity against the inactivated state of the Nav1.3 channel, with weaker activity against Nav1.5 and Nav1.7 channels. These findings provide a valuable tool for further evaluation of Nav1.3 channel as a potential drug target.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Goragot Wisedchaisri, Tamer M. Gamal El-Din, Ning Zheng, William A. Catterall
Summary: Gain-of-function mutations in the voltage-gated sodium channel NaV1.7, specifically in the S4-S5 intracellular linker, lead to severe inherited pain syndromes. Through structural analysis, it has been discovered that these mutations create new hydrogen bonds, stabilizing the activated state of the channel and causing a negative shift in voltage dependence of activation. This study provides important insights into the mechanisms behind hyperexcitability of NaV1.7 and severe pain in inherited erythromelalgia.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Anesthesiology
Jane E. Hartung, Jamie K. Moy, Emanuel Loeza-Alcocer, Vidhya Nagarajan, Ruth Jostock, Thomas Christoph, Wolfgang Schroeder, Michael S. Gold
Summary: This study characterized the high voltage-activated calcium currents in human and rat sensory neurons, revealing differences between the two species. The results showed significant differences in current density, sensitivity, and inhibition between human and rat neurons.
Article
Pharmacology & Pharmacy
Paz Duran, Santiago Loya-Lopez, Dongzhi Ran, Cheng Tang, Aida Calderon-Rivera, Kimberly Gomez, Harrison J. Stratton, Sun Huang, Ya-ming Xu, E. M. Kithsiri Wijeratne, Samantha Perez-Miller, Zhiming Shan, Song Cai, Anna T. Gabrielsen, Angie Dorame, Kyleigh A. Masterson, Omar Alsbiei, Cynthia L. Madura, Guoqin Luo, Aubin Moutal, John Streicher, Gerald W. Zamponi, A. A. Leslie Gunatilaka, Rajesh Khanna
Summary: This study identified argentatin C, a compound derived from the Native American medicinal plant Parthenium incanum, which can block the activity of voltage-gated sodium and calcium channels and has potential as a novel treatment for painful conditions. Experimental results demonstrated that argentatin C decreased ion currents and excitability in sensory neurons and relieved postsurgical pain in a mouse model. Therefore, argentatin C may serve as an alternative therapy for chronic pain management.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Scott P. Fraser, Rustem Onkal, Margaux Theys, Frank Bosmans, Mustafa B. A. Djamgoz
Summary: The neonatal splice variant of Na(V)1.5 (nNa(V)1.5) in breast and colon cancer cells can be pharmacologically distinguished from the adult counterpart (aNa(V)1.5) by specific antibodies and toxins. This finding may contribute to the development of low molecular weight compounds as non-toxic therapeutic drugs for cancers expressing nNa(V)1.5.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Eva Fuchs, David Alexander Christian Messerer, Georg Karpel-Massler, Michael Fauler, Thomas Zimmer, Bettina Jungwirth, Karl Josef Foehr
Summary: In addition to its classical anti-cancer activity, the tumor therapeutic drug TIC10 may enhance its anti-tumor properties by blocking voltage-gated sodium channels.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Britta Nubbemeyer, Ajay Abisheck Paul George, Toni Kuehl, Anna Pepanian, Maximilian Steve Beck, Rahma Maghraby, Maryam Shetab Boushehri, Maximilian Muehlhaupt, Eva Marie Pfeil, Suvi Katariina Annala, Hermann Ammer, Diana Imhof, Dehua Pei
Summary: This study reports the discovery of a family of selective peptidyl G alpha i/s modulators derived from peptide library screening and optimization. These modulators, when conjugated with a cell-penetrating peptide, showed cell-permeability and biological activity in cell-based assays. They exhibited potent guanine-nucleotide exchange modulator-like activity towards G alpha i and G alpha s. Molecular docking and dynamic simulations revealed the molecular basis of the protein-ligand interactions and their effects on GDP binding. This research demonstrates the feasibility of developing direct G alpha i/s modulators and provides a novel chemical probe for investigating cell signaling through GPCRs/G proteins.
ACS CHEMICAL BIOLOGY
(2022)
Article
Neurosciences
Aleksandar Rakovic, Dorothea Voss, Franca Vulinovic, Britta Meier, Ann-Katrin Hellberg, Carla Nau, Christine Klein, Enrico Leipold
Summary: Induced pluripotent stem cells can be used to create patient-specific in vitro models for studying Parkinson's disease and drug screening. However, current differentiation methods result in heterogeneous cell populations with low fractions of relevant dopaminergic neurons. This study utilized CRISPR/Cas9 technology to generate a reporter iPSC line and compared different differentiation protocols. The floor plate protocol was found to be the most efficient in generating electrophysiologically mature dopaminergic neurons.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Article
Chemistry, Analytical
Anna Pepanian, Paul Sommerfeld, Renata Kasprzyk, Toni Kuehl, F. Ayberk Binbay, Christoph Hauser, Reik Loeser, Robert Wodtke, Marcelina Bednarczyk, Mikolaj Chrominski, Joanna Kowalska, Jacek Jemielity, Diana Imhof, Markus Pietsch
Summary: This study presents a reliable fluorescence anisotropy-based method to determine ligands' affinity at the GTP-binding site and quantify the fraction of active G alpha i1 protein. It contributes a novel approach for future investigations of G alpha i and other G alpha protein subunits, exploring their signal transduction systems and potential biomedical applications.
ANALYTICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Sk Abdul Mohid, Karishma Biswas, TaeJun Won, Lakshmi S. Mallela, Arin Gucchait, Lena Butzke, Riddhiman Sarkar, Timothy Barkham, Bernd Reif, Enrico Leipold, Sanhita Roy, Anup K. Misra, Rajamani Lakshminarayanan, DongKuk Lee, Anirban Bhunia
Summary: In this study, we investigated the interaction between a novel antifungal drug VG16KRKP and the cell membranes of Candida albicans. We found that VG16KRKP disrupts the structural integrity of fungal membranes and exhibits broad-spectrum antifungal activity, with selectivity determined by specific amino acid side chains in the peptide sequence.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2022)
Editorial Material
Biochemistry & Molecular Biology
Diana Imhof
BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Marie-Therese Hopp, Dhruv Chetanbhai Rathod, Kristina Helena Winn, Shubhi Ambast, Diana Imhof
Summary: This study reveals that human hemoglobin can transiently bind heme through surface-exposed sequence motifs, with high heme-binding capacity and peroxidase-like activity.
BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Marie-T Hopp, Dhruv C. Rathod, Diana Imhof
Summary: In severe cases, autoimmune reactions induced by SARS-CoV-2 are associated with hemolytic complications. Hemolysis-derived heme from ruptured red blood cells can trigger fatal inflammatory and coagulant effects, potentially worsening the progression of COVID-19. Additionally, the virus itself can induce proinflammatory signals through the accessory protein 7a.
Correction
Biochemistry & Molecular Biology
Stephan Immenschuh, Diana Imhof
BIOLOGICAL CHEMISTRY
(2023)
Article
Neurosciences
Samuel Kuehs, Laura Teege, Ann-Katrin Hellberg, Christina Stanke, Natja Haag, Ingo Kurth, Robert Blum, Carla Nau, Enrico Leipold
Summary: The study presents a new method for isolating, transfecting, and electrophysiologically characterizing ENS neurons, demonstrating the feasibility of this approach in functional studies.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2022)
Article
Chemistry, Medicinal
Toni Kuehl, Maya G. Georgieva, Harald Huebner, Maria Lazarova, Matthias Vogel, Bodo Haas, Martina I. Peeva, Aneliya A. Balacheva, Ivan P. Bogdanov, Luigi Milella, Maria Ponticelli, Tsvetomir Garev, Immacolata Faraone, Roumyana Detcheva, Borislav Minchev, Polina Petkova-Kirova, Lyubka Tancheva, Reni Kalfin, Atanas G. Atanasov, Liudmil Antonov, Tamara I. Pajpanova, Kiril Kirilov, Marcus Gastreich, Peter Gmeiner, Diana Imhof, Nikolay T. Tzvetkov
Summary: The modulatory interactions between neurotensin (NT) and the dopaminergic neurotransmitter system in the brain suggest that NT may be associated with the progression of Parkinson's disease (PD). NT exerts its neurophysiological effects by interactions with the human NT receptors type 1 (hNTS1) and 2 (hNTS2). The development of NT-based analogs targeting hNTS1 and hNTS2 receptors shows potential for the treatment of PD and other CNS disorders.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Applied
Laura Fitzner, Toni Kuehl, Mario Hasler, Diana Imhof, Karin Schwarz, Julia Katharina Keppler
Summary: UVB irradiation induces protein modification, while also introducing radicals and oxidizing side chains. This study focuses on assessing the functionalization of BLG through UVB irradiation and its oxidative degradation.
Article
Chemistry, Medicinal
Anna Pepanian, Furkan Ayberk Binbay, Suchismita Roy, Britta Nubbemeyer, Amritendu Koley, Curran A. Rhodes, Hermann Ammer, Dehua Pei, Pradipta Ghosh, Diana Imhof
Summary: Novel bicyclic peptides were identified through combinatorial library screening and showed prominent properties as molecular switch-on/off modulators of Gαi signaling, with GPM-3 being the first chemically identified GAP modulator with a high binding affinity for Gαi protein. Computational analyses assessed the structure of the peptides, ligand-protein interaction sites, and their impact on the nucleotide binding site. This approach may lead to the development of efficient chemical biological probes targeting Gαi protein modulation within a cellular context.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Dhruv C. Rathod, Sonali M. Vaidya, Marie-T. Hopp, Toni Kuehl, Diana Imhof
Summary: Heme plays a dual role in biological processes, functioning as a prosthetic group of hemoproteins and also regulating biochemical pathways through transient association with proteins. However, the mechanisms of heme recognition and complex formation with target proteins are poorly understood. This report focuses on evaluating mammalian heme-regulated proteins and their heme-binding motifs (HBMs), particularly the Cys-Pro dipeptide motifs. This analysis provides insights into the sequence and structural anomalies observed during transient heme binding and protein regulation.
Article
Medicine, Research & Experimental
Adrian M. Piliponsky, Kavita Sharma, Phoenicia Quach, Alyssa Brokaw, Shayla Nguyen, Austyn Orvis, Siddhartha S. Saha, Nyssa Becker Samanas, Ravin Seepersaud, Yu Ping Tang, Emily Mackey, Gauri Bhise, Claire Gendrin, Anna Furuta, Albert J. Seo, Eric Guga, Irina Miralda, Michelle Coleman, Erin L. Sweeney, Charlotte A. Bauml, Diana Imhof, Jessica M. Snyder, Adam J. Moeser, Lakshmi Rajagopal
Summary: The study demonstrates that FXIIIA deficiency increases susceptibility to GBS infections in female mice. The presence of FXIIIA enhances host resistance to GBS infection, while inhibition of FXIIIA decreases host resistance. Sexual dimorphism and mast cells play a role in FXIIIA expression and its interactions with GBS adhesins.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Biochemistry & Molecular Biology
Marie-T Hopp, Ajay A. Paul George, Anuradha Ramoji, Anna Pepanian, Milena S. Detzel, Ute Neugebauer, Diana Imhof
Summary: Under hemolytic conditions, hemopexin scavenges toxic heme. Recent research has reassessed the heme-binding properties of hemopexin, revealing a binding affinity of about 0.32 nM and a stoichiometry of one to two heme molecules binding to hemopexin. Spectroscopic and computational methods were employed to confirm the hypothesis of multiple heme molecules binding to hemopexin and to analyze the heme-binding mode. Both hemopexin and a 66mer peptide were found to bind heme in mixed penta- and hexacoordinated states, indicating distinct criteria for heme binding and increased stability of the peptide-heme complex. These findings, supported by molecular dynamics simulations, contribute to our understanding of the molecular basis of the heme-hemopexin interaction and have implications for biomedical applications of hemopexin.
INTERNATIONAL JOURNAL OF PEPTIDE RESEARCH AND THERAPEUTICS
(2022)
Correction
Neurosciences
Lucia Privitera, Ellen L. Hogg, Matthias Gaestel, Mark J. Wall, Sonia A. L. Correa
Article
Neurosciences
Li-Ya Jiang, Guan-Hao Wang, Jing-Jiao Xu, Xiao-Li Li, Xiao-Yan Lin, Xiang Fang, Hong-Xu Zhang, Mei Feng, Chun-Ming Jiang
Summary: This study reveals the importance of LINC00473 in regulating temozolomide (TMZ) resistance in glioblastoma (GB) and its potential mechanism. By regulating the expression of CEBP alpha and MGMT, LINC00473 promotes the formation of chemoresistance. Furthermore, LINC00473 can transfer chemoresistance to adjacent sensitive cells through exosomes.
Article
Neurosciences
Olga Kopach, Tetyana Pivneva, Nataliya Fedirko, Nana Voitenko
Summary: This study found that diabetic animals exhibit severe xerostomia characterized by reduced saliva flow rate, diminished total protein content, and decreased amylase activity. The impaired saliva production in diabetes is associated with reduced and delayed intracellular Ca2+ signals in submandibular acinar cells, caused by malfunctioning mitochondria. Targeting malfunctioning mitochondria may be a potential strategy for the treatment of diabetic xerostomia.
Article
Neurosciences
Nicholas M. Timme, Cherish E. Ardinger, Seth D. C. Weir, Rachel Zelaya-Escobar, Rachel Kruger, Christopher C. Lapish
Summary: This study aimed to assess aversion-resistant drinking behavior in head-fixed mice and explore the relationship between non-consummatory behaviors and aversion-resistant drinking. The results showed that head-fixed mice exhibited heterogenous levels of aversion-resistant drinking and non-consummatory behaviors were related to the intensity of this behavior.
Article
Neurosciences
David R. Maguire, Charles P. France
Summary: Methocinnamox (MCAM) is a novel, long-acting opioid receptor antagonist that effectively decreases fentanyl self-administration and prevents opioid overdose in monkeys. The study demonstrates the potential therapeutic utility of MCAM in the treatment of opioid use disorder.
Article
Neurosciences
Xiang Li, Dan Feng, Shenglu Ma, Mingxing Li, Shulei Zhao, Man Tang
Summary: This study investigated the effects of fluoxetine on neurochemical, neurobiological, and neurobehavioral changes in different subregions of the hippocampus. The results showed that fluoxetine increased dialysate 5-HT, decreased membrane 5-HTT protein, and increased cytoplasmic fraction. Additionally, fluoxetine reduced immobility times in behavioral tests, with greater effects observed in the ventral subregion compared to the dorsal subregion.
Article
Neurosciences
Alexander V. Zholos, Mariia I. Melnyk, Dariia O. Dryn
Summary: Acetylcholine is an important neurotransmitter in visceral smooth muscles, activating M2 and M3 muscarinic receptors to cause smooth muscle excitation and contraction. This review focuses on the cellular and molecular mechanisms underlying acetylcholine-induced depolarisation and smooth muscle contraction, as well as the effects of anticholinergic drugs on gastrointestinal motility. The knowledge gained from recent studies has greatly expanded our understanding of these processes.
Article
Neurosciences
Zhenlong Li, Hsien-Yu Peng, Chau-Shoun Lee, Tzer-Bin Lin, Ming-Chun Hsieh, Cheng-Yuan Lai, Han-Fang Wu, Lih-Chyang Chen, Mei-Ci Chen, Dylan Chou
Summary: Methylone shows significant efficacy in treating depression and social deficits, making it an ideal candidate for anti-depressant medication.
Article
Neurosciences
Aline Freyssin, Allison Carles, Sarra Guehairia, Gilles Rubinstenn, Tangui Maurice
Summary: This study explores the potential of combining FENM and S1R agonists in the treatment of Alzheimer's disease. The results showed that most FENM-based combinations can protect against learning deficits caused by A beta 25-35, with better efficacy in short-term memory.
Article
Neurosciences
J. D. Lorente, J. Cuitavi, L. Rullo, S. Candeletti, P. Romualdi, L. Hipolito
Summary: This study analyzed the effects of pain on negative affect in different sexes and time courses, as well as the involvement of the dynorphinergic and corticotropin releasing factor systems in these pain-related behaviors. The results showed sex and time-dependent anxiety- and anhedonia-like behaviors induced by pain in female rats. The recruitment of KOR/DYN in the NAc was identified as a key neurological substrate mediating pain-induced behavioral alterations.
Article
Neurosciences
Rongjun Liu, Daofan Sun, Xiuzhong Xing, Qingge Chen, Bo Lu, Bo Meng, Hui Yuan, Lan Mo, Liufang Sheng, Jinwei Zheng, Qiusheng Wang, Junping Chen, Xiaowei Chen
Summary: The coexistence of pain and depression is frequently observed in patients with chronic pain and depression. Oxytocin, a neuropeptide, has been reported to relieve chronic pain and depressive symptoms. This study investigated the effect of intranasal oxytocin on neuropathic pain and comorbid depressive symptoms, and found that oxytocin attenuated depression-like behavior but did not alleviate mechanical hyperalgesia. The results suggest that intranasal oxytocin may have the potential to treat depressive symptoms in neuropathic pain patients.