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
Pharmacology & Pharmacy
Kuang-I. Cheng, Hung-Chen Wang, Kuang-Yi Tseng, Yi-Hsuan Wang, Chung-Yu Chang, Yi-Jing Chen, Chung-Sheng Lai, Dar-Ren Chen, Lin-Li Chang
Summary: Oral cilostazol can attenuate the responses of mechanical allodynia and has the potential to treat diabetic neuropathy by attenuating NaV and glial cell dysregulation.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Cell Biology
Samantha C. Salvage, Taufiq Rahman, David A. Eagles, Johanna S. Rees, Glenn F. King, Christopher L-H. Huang, Antony P. Jackson
Summary: This study investigates the influence and modulation of the Na-V-beta 3-subunit on the function of the voltage-gated sodium channel Na(V)1.7 and the effect of the toxins ProTx-II and OD1 on Na(V)1.7 function. The results show that ProTx-II slows the activation rate of Na(V)1.7, while OD1 reduces fast inactivation rate and accelerates recovery from inactivation. The presence of the beta 3-subunit partially counteracts these effects. Furthermore, OD1 induces a hyperpolarising shift in the steady-state activation voltage of Na(V)1.7, which is not observed in the presence of beta 3. The study suggests that the beta 3-subunit influences the interaction between toxins and Na(V)1.7 through indirect allosteric mechanisms.
JOURNAL OF CELLULAR PHYSIOLOGY
(2023)
Article
Pharmacology & Pharmacy
Caixue Wang, Han Hao, Kaitong He, Yating An, Zeyao Pu, Nikita Gamper, Hailin Zhang, Xiaona Du
Summary: GABAergic inhibition in the peripheral sensory ganglia weakens during the development of neuropathic pain, but the alpha 5 subunit of the GABA(A) receptor may play a unique pro-algesic role in this process. Knock-down of the alpha 5 subunit alleviates neuropathic hyperalgesia, suggesting it could be a potential therapeutic target for neuropathic pain.
FRONTIERS IN PHARMACOLOGY
(2021)
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
Biochemistry & Molecular Biology
Chan-Su Bok, Ryeong-Eun Kim, Yong-Yeon Cho, Jin-Sung Choi
Summary: This study investigated the blocking effects of tramadol on sodium currents in HEK293 cells expressing Nav1.7 and Nav1.5 channels. Tramadol inhibited both channels with IC50 values of 0.73 mM and 0.43 mM, respectively. Tramadol also shifted the steady-state inactivation curves, slowed the recovery rate, and induced stronger use-dependent inhibition. The plasma concentration of tramadol upon oral administration is unlikely to block Nav1.7 or Nav1.5 effectively, but it may act as a local anesthetic or antiarrhythmic agent at high concentrations by injection.
BIOMOLECULES & THERAPEUTICS
(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)
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
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
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
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)