Article
Biology
Peter R. Strege, Luke M. Cowan, Constanza Alcaino, Amelia Mazzone, Christopher A. Ahern, Lorin S. Milescu, Gianrico Farrugia, Arthur Beyder
Summary: Shear stress and patch suction can reversibly alter the kinetic properties and maximum current of NaChBac, suggesting it is mechanosensitive. Structural analysis reveals a large displacement of the intracellular gate, supporting the proposed mechanosensitive mechanism.
Article
Chemistry, Medicinal
Juan Antonio Contreras Vite, Carlos Vega Valle, Happi Biekeu Mbem, Sarah-Maude Boivin, Robert Dumaine
Summary: Lamotrigine is commonly used for treating bipolar disorder and epilepsy. The US FDA has recently issued a warning regarding the drug's potential to cause conduction anomalies and Brugada syndrome in epileptic patients. In this study, researchers used patch clamp technique on rat cardiomyocytes to investigate the effect of Lamotrigine on cardiac sodium current (I-Na). The results showed that Lamotrigine inhibited I-Na peak amplitude, reduced cardiac excitability, and prolonged the action potential refractory period in epileptic rats.
Article
Biochemistry & Molecular Biology
Karl Josef Foehr, Michael Rapp, Michael Fauler, Thomas Zimmer, Bettina Jungwirth, David Alexander Christian Messerer
Summary: Aripiprazole has been identified as a potent blocker of the dominant voltage-gated sodium channel of heart muscle. Its interactions with the channel differ depending on the state, with weaker affinity for the resting state and stronger affinity for the inactivated state.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Physiology
Carol J. Milligan, Lyndsey L. Anderson, Iain S. McGregor, Jonathon C. Arnold, Steven Petrou
Summary: Cannabis contains CBD and other phytocannabinoids with therapeutic potential for epilepsy. In this study, the effects of CBGA, CBDVA, CBG, CBCA, and CBC on human voltage-gated sodium channels were evaluated and compared to CBD. CBD and CBGA inhibited peak current amplitude, while CBG, CBCA, and CBC showed modest inhibition. CBDVA selectively inhibited Na(V)1.6.
FRONTIERS IN PHYSIOLOGY
(2023)
Review
Pharmacology & Pharmacy
Damian C. Bell, Luigi Leanza, Saverio Gentile, Daniel R. Sauter
Summary: Ion channels play key roles in various physiological processes, and their dysfunction can lead to channelopathies, including cancer. The field of ion channel and cancer research has rapidly grown in the past two decades, allowing us to gain deeper insights into the mechanisms of ion channels in cancer and develop therapeutic interventions.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Cell Biology
Nolan M. Dvorak, Cynthia M. Tapia, Timothy J. Baumgartner, Jully Singh, Fernanda Laezza, Aditya K. Singh
Summary: This study reveals the selective modulatory effects of Wee1 kinase inhibitor on Na(v)1.2 channel activity, emphasizing the importance of cellular signaling pathways in fine-tuning neuronal excitability.
Article
Cell Biology
Adam Feher, Marianna Pocsi, Ferenc Papp, Tibor G. Szanto, Agota Csoti, Zsolt Fejes, Bela Nagy, Balazs Nemes, Zoltan Varga
Summary: This study identified multiple voltage-gated sodium channels in the plasma membrane of human B cells using electrophysiological and molecular biology methods. The detected sodium currents showed sensitivity between TTX-sensitive and TTX-insensitive channels, suggesting the co-existence of multiple Na(V)1 subtypes. The results also supported the functional role of these channels in shaping and maintaining the resting membrane potential.
Article
Biology
Benjamin M. Zemel, Alexander A. Nevue, Leonardo E. S. Tavares, Andre Dagostin, Peter V. Lovell, Dezhe Z. Jin, Claudio V. Mello, Henrique von Gersdorff
Summary: This study investigated the excitability of upper motor neurons controlling vocal motor function in zebra finches and found that the key command neurons RAPNs exhibited higher firing rates and ultranarrow spikes. Pharmacological and molecular data revealed that RAPNs had higher expression of Kv3.1 channels. The study provides evidence that songbirds and primates have evolved the use of Kv3.1 in upper motor neurons controlling fast and complex motor skills.
Article
Biochemistry & Molecular Biology
Marcelino Cereijido, Lidia Jimenez, Lorena Hinojosa, Aida Castillo, Jacqueline Martinez-Rendon, Arturo Ponce
Summary: This study reveals a new role for ouabain as a modulator of the expression of voltage-gated potassium channels in epithelial cells, which requires cell-cell contacts.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
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
Neurosciences
Elena G. Govorunova, Oleg A. Sineshchekov, Leonid S. Brown, John L. Spudich
Summary: Channelrhodopsins are proteins that guide phototaxis and have applications in optogenetics. This study reports the use of a high-throughput automated patch-clamp platform for the characterization of ChRs, providing a more efficient method than manual patch clamping.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2022)
Review
Pharmacology & Pharmacy
Mark L. Dallas, Damian Bell
Summary: It is clear that APC technology has significantly advanced drug discovery programs, particularly in the fields of neuroscience and cardiovascular research. The challenge for the future lies in keeping up with fundamental research and improving the translation of the large datasets obtained.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Article
Biochemistry & Molecular Biology
Marta Martini, Giorgio Rispoli
Summary: Some sensory disorders in hearing, vestibular, and vision can be attributed to voltage-gated Ca2+ channels in sensory cells. In this study, the Na+ current flowing through L- and R-type Ca2+ channels in labyrinth hair cells was investigated. The activation and deactivation of the Na+ current in L-type channels were affected by low Ca2+ concentration, resulting in increased current amplitude. The R-type Na+ current was partially blocked by nifedipine and its current amplitude increased in low Ca2+ condition. Furthermore, the selectivity filter of R channels was less affected by external Ca2+ compared to L channels.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Aditya K. Singh, Nolan M. Dvorak, Cynthia M. Tapia, Angela Mosebarger, Syed R. Ali, Zaniqua Bullock, Haiying Chen, Jia Zhou, Fernanda Laezza
Summary: The voltage-gated Na+ channel plays a crucial role in the initiation and propagation of action potentials, requiring protein:protein interactions for full physiological activity. Peptides targeting the FGF14:Nav1.6 interaction have been pharmacologically evaluated and shown to modulate Nav1.6-mediated currents in a FGF14-dependent manner, suggesting potential as targeted pharmacological modulators.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Review
Pharmacology & Pharmacy
Fritz Markwardt
Summary: Patch clamp investigations help understand the molecular function of single ion channels. The human P2X7 receptor is an ATP-gated ion channel involved in inflammatory and nociceptive reactions. Specific residues and domains play crucial roles in ion channel function.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Anesthesiology
Hugo R. Arias, Han-Shen Tae, Laura Micheli, Arsalan Yousuf, Dina Manetti, Maria Novella Romanelli, Carla Ghelardini, David J. Adams, Lorenzo Di Cesare Mannelli
Summary: The study aimed to characterize the pharmacological and behavioral activity of two novel compounds, DM497 and DM490. It was found that DM497 could relieve neuropathic pain induced by oxaliplatin, while DM490 inhibited its effect at the same dose. These effects were not associated with changes in motor coordination or locomotor activity.
ANESTHESIA AND ANALGESIA
(2023)
Article
Chemistry, Multidisciplinary
Yan Zhou, Peta J. Harvey, Johannes Koehbach, Lai Yue Chan, Alun Jones, Asa Andersson, Irina Vetter, Thomas Durek, David J. Craik
Summary: In this study, a novel method using asparaginyl endopeptidase (AEP)-mediated cyclization was successfully employed to generate backbone cyclic analogues of MVIIA. These cyclic analogues showed improved pharmaceutical properties, including enhanced stability and inhibition of calcium channels. This study highlights the potential of AEP transpeptidases in cyclizing complex peptides and improving the therapeutic value of conotoxins.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biochemical Research Methods
Poanna Tran, Hue N. T. Tran, Kirsten L. McMahon, Jennifer R. Deuis, Lotten Ragnarsson, Alexander Norman, Simon J. Sharpe, Richard J. Payne, Irina Vetter, Christina I. Schroeder
Summary: This study aimed to design new bivalent inhibitors of Na(V)1.7 by combining the pore blocking activity of conotoxins with the gating modifier activity of spider toxins. The potency and selectivity of the resulting bivalent toxins were evaluated by ligating a conotoxin to a spider toxin. The bivalent peptide Pro[LPATG(6)]Sx, resulting from the ligation of ProTx-II and SxIIIC, showed the best combination with conserved potency at hNa(V)1.7.
BIOCONJUGATE CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Lydia J. Bye, Rocio K. Finol-Urdaneta, Han-Shen Tae, David J. Adams
Summary: Nicotinic acetylcholine receptors (nAChRs) expressed in microglia play a crucial role in regulating immune functions through the cholinergic anti-inflammatory pathway. Dysregulation of this pathway can lead to neuroinflammation associated with neurodegenerative diseases. Disease-associated microglia exhibit an altered phenotype characterized by enhanced defense functions and impaired nurturing and repairing functions. Cholinergic modulation of neuroinflammation holds promise as a potential treatment avenue.
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
(2023)
Article
Medicine, Research & Experimental
Rocio K. Finol-Urdaneta, Jeffrey R. McArthur, Ashraf Aboelela, Richard S. Bujaroski, Hiwa Majed, Alejandra Rangel, David J. Adams, Marie Ranson, Michael J. Kelso, Benjamin J. Buckley
Summary: Acid-sensing ion channels (ASICs) are transmembrane sensors of extracellular acidosis and potential drug targets. In this study, 6-iodoamiloride was identified as a potent inhibitor of ASIC1 and ASIC3, showing improved inhibitory activity compared to amiloride. This compound can be used to study the effects of ASIC inhibition on cell physiology.
MOLECULAR PHARMACEUTICS
(2023)
Article
Chemistry, Organic
Hue N. T. Tran, Elena Budusan, Natalie J. Saez, Alexander Norman, Isaac J. Tucker, Glenn F. King, Richard J. Payne, Lachlan D. Rash, Irina Vetter, Christina I. Schroeder
Summary: Hi1a is a naturally occurring bivalent spider-venom peptide that shows promise for limiting ischemic damage. However, challenges in synthesizing and producing the peptide in large quantities have hindered progress in this area. Access to synthetic Hi1a is crucial for its development as a pharmacological tool and potential therapeutic.
Article
Multidisciplinary Sciences
Aymeric Rogalski, S. W. A. Himaya, Richard J. Lewis
Summary: This study documents the culture of Conus magus and reveals dramatic shifts in predatory feeding behavior between post-metamorphic juveniles and adult specimens. The research found that early juveniles exclusively feed on polychaete worms using a unique sting-and-stalk foraging behavior, while adults capture fish using venom peptides and a hooked radular tooth.
NATURE COMMUNICATIONS
(2023)
Article
Food Science & Technology
Michael J. J. Holmes, Richard J. J. Lewis
Summary: Published data were used to model the transfer of ciguatoxins across different levels of a marine food chain on the Great Barrier Reef, Australia. The study found that even transient and sparse ciguatoxin producers can generate ciguateric fishes. The research provides insights for designing risk and mitigation strategies for ciguatera and exploring different scenarios for the accumulation and transfer of ciguatoxins in marine food chains.
Article
Pharmacology & Pharmacy
Thao N. T. Ho, Nikita Abraham, Richard J. Lewis
Summary: This study describes the allosteric binding mode of the granulin-like C-terminal (CTD) of VxXXB bound to Lymnea stagnalis acetylcholine binding protein (Ls-AChBP), revealing a novel allosteric binding site for nAChR antagonists. The results provide new structural insight into the allosteric mechanism of nAChR inhibition and define the cooperative binding mode of aD-conotoxins' N-terminal domain linked granulin core domains.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Han-Shen Tae, Marcelo O. Ortells, Bassel J. Tekarli, Dina Manetti, Maria Novella Romanelli, J. Michael McIntosh, David J. Adams, Hugo R. Arias
Summary: The study aimed to investigate the pharmacological activity and molecular mechanism of a novel ibogamine derivative, DM506, on different subtypes of nicotinic acetylcholine receptors (nAChRs). The results showed that DM506 inhibits ACh-evoked currents at rat nAChR subtypes in a non-competitive manner. The inhibition selectivity of DM506 follows a specific sequence, and it interacts with specific sites on the nAChRs. This study reveals that DM506 inhibits both α9α10 and α7 nAChR subtypes through novel allosteric mechanisms, involving modulation of extracellular-transmembrane and cytoplasmic domains.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Chemistry, Medicinal
Edin Muratspahic, Andrew M. White, Cosmin I. Ciotu, Nadine Hochrainer, Natasa Tomasevic, Johannes Koehbach, Richard J. Lewis, Mariana Spetea, Michael J. M. Fischer, David J. Craik, Christian W. Gruber
Summary: This study developed a novel KOR antagonist using peptide stapling and demonstrated its high selectivity and competitive antagonistic effect. The findings provide valuable insights for the development of innovative peptide drugs for KOR-related illnesses.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Rocio K. Finol-Urdaneta, Boris S. Zhorov, Daniel G. Baden, David J. Adams
Summary: In this study, the effects of brevetoxins (PbTx) and brevenal on Nav channel function were investigated. PbTx-3 was found to be over 1000-fold more potent than brevenal in modulating Nav channels. Additionally, the presence of brevenal in the intracellular solution reduced the sensitivity of Nav channels to PbTx-3. A computational model of the interaction between PbTx-2 and Nav1.2 was generated. These findings provide valuable insights into the functional modulation of Nav channels by PbTx and brevenal, and may have implications for the development of new Nav channel modulators with therapeutic applications.
Article
Food Science & Technology
Jamila Ahmed, Andrew A. Walker, Hugo D. Perdomo, Shaodong Guo, Samantha A. Nixon, Irina Vetter, Hilary I. Okoh, Dalhatu M. Shehu, Mohammed N. Shuaibu, Iliya S. Ndams, Glenn F. King, Volker Herzig
Summary: The control of diseases transmitted by Aedes aegypti mainly relies on chemical insecticides, but insecticide resistance in A. aegypti hampers the effectiveness of current control measures. To address this issue, researchers screened spider and scorpion venoms for mosquitocidal toxins, and identified two peptides from the venom of Lasiodora klugi tarantula with activity against adult A. aegypti. These peptides, named U-TRTX-Lk1a and U-TRTX-Lk2a, have the potential to serve as novel control agents for A. aegypti.
Review
Food Science & Technology
Ivannah Pottier, Richard J. Lewis, Jean-Paul Vernoux
Summary: Ciguatera is a widespread poisoning caused by eating marine fish and invertebrates contaminated with ciguatoxins. The various types of ciguatoxins and their properties have been studied extensively, but there is no standardized method for extracting and quantifying ciguatoxins due to limited reference materials. Recent advances in analysis techniques offer new opportunities for detecting and quantifying ciguatoxins, but further research is needed to understand their toxicity and role in ciguatera fish poisoning.
Article
Chemistry, Multidisciplinary
Poanna Tran, Theo Crawford, Lotten Ragnarsson, Jennifer R. Deuis, Mehdi Mobli, Simon J. Sharpe, Christina I. Schroeder, Irina Vetter
Summary: Multiple spider venom-derived gating modifier toxins exhibit conformational heterogeneity during purification by RP-HPLC. This phenomenon, often attributed to proline cis/trans isomerization, has also been observed in peptides without a proline residue. Pn3a is one such peptide forming two distinguishable peaks that readily interconvert. In this study, an N-terminal modification of Pn3a allowed the isolation of the conformers and revealed that the earlier-eluting conformer is inactive and disordered, while the later-eluting conformer is active with a rigid structure corresponding to the published structure of Pn3a. The exchange is pH-dependent and may be caused by reversible disruption and formation of intramolecular salt bridges.
Article
Pharmacology & Pharmacy
Paola Orlandi, Marta Banchi, Francesca Vaglini, Marco Carli, Stefano Aringhieri, Arianna Bandini, Carla Pardini, Cristina Viaggi, Michele Lai, Greta Ali, Alessandra Ottani, Eleonora Vandini, Patrizia Guidi, Margherita Bernardeschi, Veronica La Rocca, Giulio Francia, Gabriella Fontanini, Mauro Pistello, Giada Frenzilli, Daniela Giuliani, Marco Scarselli, Guido Bocci
Summary: This study investigates the role of MC4R in melanoma and the use of the selective antagonist ML in combination with vemurafenib. The results show that ML can inhibit melanoma cell proliferation and induce apoptosis through the inhibition of ERK1/2 phosphorylation and reduction of BCL-XL expression. The combination of vemurafenib and ML exhibits a synergistic effect in vitro and inhibits tumor growth in vivo without causing adverse effects.
BIOCHEMICAL PHARMACOLOGY
(2024)
Article
Pharmacology & Pharmacy
Conor J. Bloxham, Katina D. Hulme, Fabrizio Fierro, Christian Fercher, Cassandra L. Pegg, Shannon L. O'Brien, Simon R. Foster, Kirsty R. Short, Sebastian G. B. Furness, Melissa E. Reichelt, Masha Y. Niv, Walter G. Thomas
Summary: Bitter taste receptors (T2Rs) are a type of G protein-coupled receptors that allow humans to detect aversive and toxic substances. This study characterized the functional properties of previously identified T2Rs in human cardiac tissues and their naturally occurring polymorphisms. The results showed differences in signaling among different T2R variants, and revealed a potential association between the T2R50 Tyr203 variant and cardiovascular disease.
BIOCHEMICAL PHARMACOLOGY
(2024)
Article
Pharmacology & Pharmacy
Lu Chen, Huanying Shi, Wenxin Zhang, Yongjun Zhu, Haifei Chen, Zimei Wu, Huijie Qi, Jiafeng Liu, Mingkang Zhong, Xiaojin Shi, Tianxiao Wang, Qunyi Li
Summary: This study demonstrates that Carfilzomib exhibits potent anti-tumor activity against esophageal squamous cell carcinoma (ESCC) by triggering mitochondrial apoptosis and reprogramming cellular metabolism. It has been identified that activating transcription factor 3 (ATF3) plays a crucial role as a cellular target in ESCC cells treated with Carfilzomib. Overexpression of ATF3 effectively counteracts the effects of Carfilzomib on ESCC cell proliferation, apoptosis, and metabolic reprogramming. Furthermore, ATF3 mediates the anti-tumor activity of Carfilzomib, suggesting its potential as a therapeutic agent for ESCC.
BIOCHEMICAL PHARMACOLOGY
(2024)
Review
Pharmacology & Pharmacy
Xing Zhang, Xiang Li, Ran Xia, Hong-Sheng Zhang
Summary: This review summarizes recent progress on the mechanisms of ferroptosis resistance in cancer and highlights the role of redox status and metabolism. Combination therapy for ferroptosis has great potential in treating resistant malignant tumors.
BIOCHEMICAL PHARMACOLOGY
(2024)