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.
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)
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
Chemistry, Medicinal
Eleni Kaisis, Laura J. J. Thei, Gary J. J. Stephens, Mark L. L. Dallas
Summary: Cav2.2 channels are modulated by Ab(1-42) peptides, and this modulation has different effects at different concentrations. This study reveals a potential mechanistic link between amyloid accumulation and Cav2.2 channel modulation.
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)
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
Biophysics
Mara Almog, Nurit Degani-Katzav, Alon Korngreen
Summary: Ion channel kinetics are highly sensitive to temperature changes, but most investigations are conducted at room temperature. In this study, the kinetics of voltage-gated sodium channels were modeled using recordings of sodium currents from rat neocortical pyramidal neurons at different temperatures, revealing different temperature dependencies for activation and inactivation.
EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS
(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)
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)
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
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
Agriculture, Multidisciplinary
Tatsuya Suzuki, Seiji Yamato
Summary: Oxazosulfyl is a novel insecticide that acts by blocking voltage-gated sodium channels in insects, resulting in paralysis. This discovery sheds light on the mode of action of oxazosulfyl as a potential pest control agent in rice fields.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2021)
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)
Article
Pharmacology & Pharmacy
Yashad Dongol, Phil M. Choi, David T. Wilson, Norelle L. Daly, Fernanda C. Cardoso, Richard J. Lewis
Summary: Through screening Australian spider venom, a peptide inhibiting Na-V channels was isolated, showing effects on various neuronal subtypes and potential for developing subtype selective inhibitors in the future.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biology
Yucheng Xiao, Jonathan W. Theile, Agnes Zybura, Yanling Pan, Zhixin Lin, Theodore R. Cummins
Summary: In this study, the authors demonstrate that I-NaR can be reconstituted in a heterologous system by coexpression of sodium channel alpha-subunits and A-type fibroblast growth factor homologous factors (FHFs). They also identify the N-terminus of FHF as the critical molecule responsible for A-type FHFs-mediated I-NaR. Moreover, knockdown of FHF4A significantly reduces I-NaR amplitude and suppresses excitability in nociceptive sensory neurons.
Article
Chemistry, Medicinal
Kang Ding, Shiqiu Yin, Zhongwei Li, Shiju Jiang, Yang Yang, Wenbiao Zhou, Yingsheng Zhang, Bo Huang
Summary: This study reports the first use of experimental electron density (ED) in the Protein Data Bank for modeling noncovalent interactions (NCIs) in protein-ligand complexes. The methodology is based on reduced electron density gradient (RDG) theory, which describes intermolecular NCIs using ED and its first derivative. An Experimental NCI Database (ExptNCI) was established, containing ED saddle points representing around 200,000 NCIs from over 12,000 protein-ligand complexes. The database can provide details on experimentally observed NCIs and support future studies and development of artificial intelligence models for protein-ligand binding prediction.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
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
Multidisciplinary Sciences
Zhenglai Zhang, Huiwen Chen, Ze Geng, Zhuoya Yu, Hang Li, Yanli Dong, Hongwei Zhang, Zhuo Huang, Juquan Jiang, Yan Zhao
Summary: In this study, cryo-EM structures of human EAAT2 in complexes with glutamate or selective inhibitor WAY-213613 were reported, providing important insights into substrate recognition and selective inhibition.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Liming Yan, Yucen Huang, Ji Ge, Zhenyu Liu, Pengchi Lu, Bo Huang, Shan Gao, Junbo Wang, Liping Tan, Sihan Ye, Fengxi Yu, Weiqi Lan, Shiya Xu, Feng Zhou, Lei Shi, Luke W. Guddat, Yan Gao, Zihe Rao, Zhiyong Lou
Summary: This study reveals the mechanism of SARS-CoV-2 RNA capping and provides atomic resolution structural details. It shows that the NiRAN domain plays a crucial role in RNAylation and the formation of GpppA. Moreover, triphosphorylated nucleotide analog inhibitors can inhibit RNAylation and GpppA formation by binding to nsp9. The conformational shift of the S-loop in NiRAN observed in the presence of sofosbuvir monophosphate suggests a possible mechanism for designing inhibitors.
Article
Biochemistry & Molecular Biology
Junping Fan, Linghan Hu, Zongwei Yue, Daohong Liao, Fusheng Guo, Han Ke, Daohua Jiang, Yong Yang, Xiaoguang Lei
Summary: The TRPV3 channel has important roles in skin physiology. Trpvicin, identified in this study, is a potent and subtype-selective inhibitor of TRPV3, which shows pharmacological potential in the inhibition of itch and hair loss. The research provides mechanistic insights into the inhibition of TRPV3 by Trpvicin and supports drug development targeting TRPV3.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Food Science & Technology
Ruixue Zhang, Jiangtao Zhang, Yan Liu, Lei Fang, Ying Wei, Ruizeng Gu, Min Lin, Liang Chen, Zhengfu Zhou
Summary: Supplementation of FWPH improves anti-fatigue ability, enhances exercise performance, and alters intestinal flora composition.
JOURNAL OF FUNCTIONAL FOODS
(2022)
Article
Multidisciplinary Sciences
Lvwei Wang, Rong Bai, Xiaoxuan Shi, Wei Zhang, Yinuo Cui, Xiaoman Wang, Cheng Wang, Haoyu Chang, Yingsheng Zhang, Jielong Zhou, Wei Peng, Wenbiao Zhou, Bo Huang
Summary: This study reports the use of experimental electron density as training data to generate drug-like three-dimensional molecules based on the structure of a target protein pocket. The model can generate molecules with similar structures to active compounds and can be used in high-throughput virtual screening and fragment-based drug design.
SCIENTIFIC REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Jiangtao Zhang, Yiqiang Shi, Zhuo Huang, Yue Li, Bei Yang, Jianke Gong, Daohua Jiang
Summary: This study reports the cryo-EM structures of Na(V)1.7 in complexes with three pore blockers, elucidating the mechanisms of their modulation on Na(V)1.7. The findings have important implications for developing subtype-selective analgesics.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Yue Li, Tian Yuan, Bo Huang, Feng Zhou, Chao Peng, Xiaojing Li, Yunlong Qiu, Bei Yang, Yan Zhao, Zhuo Huang, Daohua Jiang
Summary: In this study, the cryo-EM structures of human Na(V)1.6/beta 1/beta 2 alone and complexed with 4,9-ah-TTX were determined, providing insights into the molecular mechanism of Na(V)1.6 inhibition and ion conductance.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Sina Jami, Jennifer R. Deuis, Tabea Klasfauseweh, Xiaoyang Cheng, Sergey Kurdyukov, Felicity Chung, Andrei L. Okorokov, Shengnan Li, Jiangtao Zhang, Ben Cristofori-Armstrong, Mathilde R. Israel, Robert J. Ju, Samuel D. Robinson, Peng Zhao, Lotten Ragnarsson, Asa Andersson, Poanna Tran, Vanessa Schendel, Kirsten L. McMahon, Hue N. T. Tran, Yanni K. -Y. Chin, Yifei Zhu, Junyu Liu, Theo Crawford, Saipriyaa Purushothamvasan, Abdella M. Habib, David A. Andersson, Lachlan D. Rash, John N. Wood, Jing Zhao, Samantha J. Stehbens, Mehdi Mobli, Andreas Leffler, Daohua Jiang, James J. Cox, Stephen G. Waxman, Sulayman D. Dib-Hajj, G. Gregory Neely, Thomas Durek, Irina Vetter
Summary: This study demonstrates the essential role of TMEM233 in the activity of stinging nettle toxins and its modulation of gating properties of Na(V)1.7. These findings identify TMEM233 as an interacting protein of Na(V)1.7, position TMEM233 and dispanins as indispensable accessory proteins for toxin-mediated effects on Na-V channel gating, and provide important insights into the function of Na-V channels in sensory neurons.
NATURE COMMUNICATIONS
(2023)
Article
Cell Biology
Jiangtao Zhang, Shiqi Liu, Junping Fan, Rui Yan, Bo Huang, Feng Zhou, Tian Yuan, Jianke Gong, Zhu Huang, Daohua Jiang
Summary: In this study, cryoelectron microscopy was used to obtain structures of the Slo2.2 channel in closed, open, and inhibitor-bound form, providing insights into its cation regulation and inhibition. The closed state of Slo2.2 contains multiple K+ and Zn2+ binding sites in the cytoplasmic gating ring domain, which stabilize the closed conformation. The open state reveals Na+-sensitive sites that induce gating ring expansion and rotation upon Na+ binding, leading to inner gate opening. Additionally, a potent inhibitor blocks the pore by binding to a pocket formed by the pore helix and S6 helix. These findings establish a structural framework for studying Slo2.2 channel gating, Na+ sensation, and inhibition.
Article
Multidisciplinary Sciences
Sina Jami, Jennifer R. Deuis, Tabea Klasfauseweh, Xiaoyang Cheng, Sergey Kurdyukov, Felicity Chung, Andrei L. Okorokov, Shengnan Li, Jiangtao Zhang, Ben Cristofori-Armstrong, Mathilde R. Israel, Robert J. Ju, Samuel D. Robinson, Peng Zhao, Lotten Ragnarsson, Asa Andersson, Poanna Tran, Vanessa Schendel, Kirsten L. McMahon, Hue N. T. Tran, Yanni K. -Y. Chin, Yifei Zhu, Junyu Liu, Theo Crawford, Saipriyaa Purushothamvasan, Abdella M. Habib, David A. Andersson, Lachlan D. Rash, John N. Wood, Jing Zhao, Samantha J. Stehbens, Mehdi Mobli, Andreas Leffler, Daohua Jiang, James J. Cox, Stephen G. Waxman, Sulayman D. Dib-Hajj, G. Gregory Neely, Thomas Durek, Irina Vetter
Summary: TMEM233 protein is essential for the activity of ExTxA toxin on Na-V channels, and co-expression of TMEM233 modulates the gating properties of Na(V)1.7.
NATURE COMMUNICATIONS
(2023)