Article
Pharmacology & Pharmacy
Ian H. H. Kimball, Phuong T. T. Nguyen, Baldomero M. M. Olivera, Jon T. T. Sack, Vladimir Yarov-Yarovoy
Summary: In this study, the interactions between mu-Conotoxin KIIIA and the human Na(V)1.7 channel were investigated using Rosetta computational modeling and in silico docking. The specific pairwise contacts between KIIIA and hNa(V)1.7 were predicted using RosettaDock and experimentally validated. Comparison with the cryo-EM structure of KIIIA-hNa(V)1.2 revealed important similarities and differences between Na-V channel subtypes, which may have implications for understanding the molecular mechanism of toxin block. The integrative approach used in this study suggests that Rosetta structural predictions can be useful for designing biologics targeting specific Na-V channels.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Guangsi Meng, Serdar Kuyucak
Summary: This study aims to improve the affinity and blocking capacity of mu-conotoxin KIIIA for Na(V)1.2 through computational studies. After molecular modeling and simulations on the Na(V)1.2-KIIIA complex, the S5R, S6D, and S13K mutations were identified as the most promising for additional contacts, which could enhance the affinity of KIIIA for Na(V)1.2 and enable complete blocking of the channel.
Article
Chemistry, Multidisciplinary
Zixuan Lu, Chiara Barberio, Ana Fernandez-Villegas, Aimee Withers, Alexandra Wheeler, Konstantinos Kallitsis, Eleonora Martinelli, Achilleas Savva, Becky M. Hess, Anna-Maria Pappa, Gabriele S. Kaminski Schierle, Roisin M. Owens
Summary: This work reports a new system that integrates neuron membranes with organic microelectrode arrays for drug studies targeting neuronal ion channels. The system overcomes the challenges of traditional methods and provides an easy-to-test, rapid, ultra-sensitive, cell-free, and high-throughput platform to monitor dose-dependent ion-channel blocking effects on native neuronal membranes.
Article
Food Science & Technology
Kirsten L. McMahon, Hue N. T. Tran, Jennifer R. Deuis, David J. Craik, Irina Vetter, Christina Schroeder
Summary: mu-Conotoxins are peptide inhibitors of Na(V)1.7 channel with potential analgesic effects. Different mu-Conotoxins show varying selectivity towards hNa(V)1.7, with variations in loop 3 residue number and charged residues in this region affecting the selectivity. Additionally, the loop 1 extension in SxIIIC improves the inhibitory potency at hNa(V)1.7 compared to KIIIA.
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
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
Christopher Katnik, Javier Cuevas
Summary: The study focuses on intracellular ionic imbalance resulting from ischemic stroke, and the impact of NKCC1 antagonists on Na+ and Ca2+ overload. Loop diuretics BMN and EA inhibited ischemia-acidosis induced Ca2+ overload, but did not reduce Na+ increases.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Hue N. T. L. Tran, Kirsten R. McMahon, Jennifer Deuis, Irina I. Vetter, Christina Schroeder
Summary: This study evaluated the synthesis, potency, sodium channel subtype selectivity, and 3D structure of three isomers of mu-conotoxin KIIIA, and found that the disulfide bond structure affects the potency and subtype selectivity of mu-conotoxins targeting sodium channel subtypes.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Neurosciences
Daniel M. DuBreuil, Eduardo Javier Lopez Soto, Simon Daste, Remy Meir, Daniel Li, Brian Wainger, Alexander Fleischmann, Diane Lipscombe
Summary: Functional Ca(V)2.2 channels in peripheral axons innervating skin are required for capsaicin-induced heat hypersensitivity, which may be an important therapeutic target for certain forms of chronic pain.
JOURNAL OF NEUROSCIENCE
(2021)
Review
Biochemistry & Molecular Biology
Silvia Cassinelli, Carla Vinola-Renart, Anna Benavente-Garcia, Maria Navarro-Perez, Jesusa Capera, Antonio Felipe
Summary: Protein lipidation is a common form of posttranslational modification that regulates various aspects of a protein's physiology, including its structure, stability, and interaction with cellular membranes. Palmitoylation, the addition of long saturated fatty acid chains to proteins, is a key form of lipidation. Enzymes called acyltransferases and thioesterases control the behavior of palmitoylated proteins through a series of acylation and deacylation cycles. Palmitoylation plays a pleiotropic role in regulating the trafficking, spatial organization, and electrophysiological properties of ion channels, particularly voltage-gated ion channels (VGICs). Dysregulation of palmitoylation in VGICs and associated subunits is linked to the development of diseases such as cancer and mental disorders. Therefore, protein palmitoylation is emerging as an important factor in cellular protein regulation and human health.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(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
Biochemistry & Molecular Biology
Zitong Zhao, Teng Pan, Shen Chen, Peta J. Harvey, Jinghui Zhang, Xiao Li, Mengke Yang, Linhong Huang, Shoushi Wang, David J. Craik, Tao Jiang, Rilei Yu
Summary: mu-Conotoxin KIIIA is a selective blocker of sodium channels with strong inhibitory activity against Nav1.7. Its structural modification and synthesis are challenging due to the presence of three pairs of disulfide bonds. In this study, three KIIIA analogues with one disulfide bond deleted were designed and synthesized. Among them, analogue KIIIA-1 showed the highest inhibitory activity on hNav1.7. A computational model was used to determine its binding pattern to hNav1.7 and guide the design of second and third-generation analogues. Peptide 37, the most potent analogue, exhibited significantly improved inhibitory activity on hNav1.7 and demonstrated potent analgesic effects in an in vivo pain model.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Neurosciences
Victoria Gonzalez Sabater, Mark Rigby, Juan Burrone
Summary: In this study, the initiation and propagation of action potentials (APs) along the axon were investigated using genetically encoded voltage indicators (GEVIs) in dissociated hippocampal neurons from rat embryos. It was found that APs became sharper and exhibited greater fidelity as they traveled towards distal axonal domains. Blocking voltage-gated potassium channels (K-v) resulted in an increase in AP width, especially in distal locations, suggesting that higher levels of Kv channel activity in distal axons contribute to maintaining AP fidelity.
JOURNAL OF NEUROSCIENCE
(2021)
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
Chemistry, Multidisciplinary
Gaoang Wang, Jiahui Yu, Hongyan Du, Chao Shen, Xujun Zhang, Yifei Liu, Yangyang Zhang, Dongsheng Cao, Peichen Pan, Tingjun Hou
Summary: As an important member of ion channels family, the voltage-gated sodium channel is associated with various diseases. Researchers have developed the first open-source database for voltage-gated sodium channels, providing comprehensive compound data for users to search and query.
JOURNAL OF CHEMINFORMATICS
(2022)