Article
Multidisciplinary Sciences
Linus J. Conrad, Peter Proks, Stephen J. Tucker
Summary: This passage discusses a voltage-dependent gating process in the TREK-2 K+ channel, which can be modulated by small molecule agonists and high internal K+ concentrations. It is found that high ionic-strength can inhibit the channel conductance, while the activatory effect of BL1249 on channel open probability persists under these conditions. The influence of negatively charged activators like BL1249 on permeation is consistent with an electrostatic mechanism, suggesting complexity in their effect on channel gating.
Article
Biochemistry & Molecular Biology
Kaihua Zhang, David Julius, Yifan Cheng
Summary: This study utilized cryo-EM to visualize conformational transitions of TRPV1, revealing the dynamic transitions of its selectivity filter in response to algogenic agents. The findings also demonstrate a general framework for understanding how TRP channels function as polymodal signal integrators.
Article
Biophysics
Adisorn Panasawatwong, Tanadet Pipatpolkai, Stephen J. Tucker
Summary: In this study, we investigated the binding mechanism and induced conformational transitions of TREK-1 channel with PIP2 in both up and down states using simulations. Our results suggest that the binding of PIP2 to sites involving the proximal C-terminus is state-dependent, and PIP2 can promote a conformational transition from the down state to a state resembling the up state.
BIOPHYSICAL JOURNAL
(2022)
Article
Physiology
Peter Proks, Marcus Schewe, Linus J. Conrad, Shanlin Rao, Kristin Rathje, Karin E. J. Rodstrom, Elisabeth P. Carpenter, Thomas Baukrowitz, Stephen J. Tucker
Summary: The antidepressant fluoxetine and its metabolite norfluoxetine inhibit the activity of TREK channels by affecting channel gating and filter stability, regardless of the positive charge of norfluoxetine. The inhibition of NFx is not only related to the equilibrium between up and down conformations but also to the filter stability and an intrinsic voltage-dependent gating process within the filter, providing further insights into the complex allosteric mechanisms that modulate filter gating in TREK K2P channels.
JOURNAL OF GENERAL PHYSIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Yvonne Walsh, Michael Leach, Emma L. Veale, Alistair Mathie
Summary: In this study, the inhibitory effects of the anticonvulsant lamotrigine, sipatrigine, and CEN-092 on TREK and TRESK K2P channels were investigated. Sipatrigine was found to be a more potent inhibitor compared to lamotrigine, with slight differences in potency between TREK-1 and TRESK channels. Mutation of certain residues affected the inhibition by sipatrigine and lamotrigine, indicating different mechanisms of action for these compounds.
BIOCHEMISTRY AND BIOPHYSICS REPORTS
(2021)
Article
Clinical Neurology
Eduardo Benarroch
Summary: Nociceptive dorsal root ganglion (DRG) and trigeminal neurons express a variety of ion channels that play a crucial role in pain perception. Imbalance in these channels can lead to neuropathic pain, hyperalgesia, and allodynia. Voltage-gated potassium channels (K-v) and 2-pore domain potassium channels (K2P) are potential targets for developing new analgesic compounds.
Article
Neurosciences
Robert A. Rietmeijer, Ben Sorum, Baobin Li, Stephen G. Brohawn
Summary: TRAAK is a mechanosensitive two-pore domain K+ (K2P) channel essential for mechanical and thermal allodynia in neurons, with distinct conductance, kinetics, and structural differences between basal and mechanically gated openings. Understanding these dual modes of activity could lead to the development of state-selective pharmacology for potential disease treatment.
Article
Biochemistry & Molecular Biology
Bryan VanSchouwen, Jinfeng Huang, Ubaidullah Baryar, Giuseppe Melacini, Jung Ah Byun
Summary: This study reveals significant differences in the allosteric networks of the essential CBDs between the Plasmodium falciparum cGMP-dependent protein kinase (pfPKG) and human cGMP-dependent protein kinase (hPKG). The findings provide crucial insights into potential drug targets for selective inhibition of pfPKG versus hPKG, which could help reduce side effects in malaria treatments.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Clinical Neurology
Yang Yang, Chiyi Wang, Jin Liu, Daqing Liao, Wensheng Zhang, Cheng Zhou
Summary: The purpose of this study was to investigate the long-acting mechanism of LL-1 both in vivo and in vitro. The results showed that LL-1 had a faster onset and longer duration compared to QX-OH or LB alone, with no difference in local toxicity. In the patch-clamping recordings, LL-1 demonstrated additive and stable inhibition of Na-v currents.
JOURNAL OF PAIN RESEARCH
(2022)
Review
Neurosciences
Alexandra Manolache, Alexandru Babes, Ramona Madalina Babes
Summary: TRPA1, cloned in 2003, has received increasing attention for its role in pain signaling and disease states over the last 17 years. While evidence of non-neuronal expression is accumulating, its presence in nociceptive nerve endings is of central focus due to potential clinical implications. Current research has mainly focused on its role in detecting irritants, cold, and mechanical stimuli, with its chemosensory function and involvement in oxidative stress well established, while other sensory features remain unclear. Further discussion is needed on the experimental evidence for TRPA1's physiological roles in mammals, especially in humans.
NEUROSCIENCE LETTERS
(2021)
Article
Physiology
Elena B. Riel, Bjoern C. Juers, Soenke Cordeiro, Marianne Musinszki, Marcus Schewe, Thomas Baukrowitz
Summary: Riel et al. screened K+ channels of the K-2P family for sensitivity to polyanionic lipids, such as PIP2 and oleoyl-CoA. They show that these lipids activate or inhibit individual channels with different affinity and establish them as potential effectors to regulate channel activity.
JOURNAL OF GENERAL PHYSIOLOGY
(2021)
Article
Pharmacology & Pharmacy
Fang Hu, Xu Cao, Canyang Niu, KeWei Wang
Summary: The coassembly of TRPV3 and TRPV4 channels into heterotetrameric complexes increases the functional diversity within the channel subfamily and may play a role in fine-tuning environmental detection and temperature sensation in mammals.
MOLECULAR PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Do Hoon Kwon, Feng Zhang, Justin G. Fedor, Yang Suo, Seok-Yong Lee
Summary: The study used thermal titration methods and cryo-EM to elucidate the conformational trajectory of the vanilloid receptor TRPV1 with resiniferatoxin (RTx) bound. The results showed that RTx binding induced a sequential conformational wave in TRPV1, opening the intracellular gate first, followed by selectivity filter dilation and pore loop rearrangement to reach the final open state. Understanding this RTx-mediated long-range allostery in TRPV1 could enhance the therapeutic potential of RTx for pain relief in advanced cancer or knee arthritis.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Wendy W. Liu, Tyler G. Kinzy, Jessica N. Cooke Bailey, Zihe Xu, Pirro Hysi, Janey L. Wiggs, NEIGHBORHOOD Consortium
Summary: This study investigated the associations between gene variants of mechanosensitive ion channels and primary open-angle glaucoma (POAG), a disease modulated by eye pressure. The researchers identified several rare and common variants in these ion channel genes that showed associations with POAG, suggesting these channels may be potential therapeutic targets.
SCIENTIFIC REPORTS
(2023)
Article
Mathematics, Applied
Zhen Li, Jian Dong, Yiming Luo, Min Liu, Dingfang Li
Summary: In this paper, a well-balanced and positive-preserving nonstaggered central scheme is proposed for open-channel flows with variable channel width and nonflat bottom. Numerical experiments demonstrate that the scheme has high accuracy and stability.
MATHEMATICAL METHODS IN THE APPLIED SCIENCES
(2023)
Article
Endocrinology & Metabolism
Conor McClenaghan, Novella Rapini, Domenico Umberto De Rose, Jian Gao, Jacob Roeglin, Carla Bizzarri, Riccardo Schiaffini, Eloisa Tiberi, Mafalda Mucciolo, Annalisa Deodati, Alessandro Perri, Giovanni Vento, Fabrizio Barbetti, Colin G. Nichols, Stefano Cianfarani
Summary: The study identified a previously uncharacterized KCNJ11 gene mutation that causes neonatal diabetes with developmental delay. The mutation reduces ATP inhibition, resulting in a significant gain-of-function in K-ATP channels and loss of sensitivity to sulfonylurea therapy in the patient.
HORMONE RESEARCH IN PAEDIATRICS
(2022)
Article
Neurosciences
Soma S. Singareddy, Helen Roessler, Conor McClenaghan, Jennifer M. Ikle, Robert C. Tryon, Gijs Haaften, Colin G. Nichols
Summary: ATP-sensitive potassium channels play a crucial role in cellular metabolism and excitability in the heart and vasculature. Zebrafish models offer insights into the link between molecular dysfunction and complex pathophysiology.
JOURNAL OF PHYSIOLOGY-LONDON
(2022)
Article
Biophysics
Adisorn Panasawatwong, Tanadet Pipatpolkai, Stephen J. Tucker
Summary: In this study, we investigated the binding mechanism and induced conformational transitions of TREK-1 channel with PIP2 in both up and down states using simulations. Our results suggest that the binding of PIP2 to sites involving the proximal C-terminus is state-dependent, and PIP2 can promote a conformational transition from the down state to a state resembling the up state.
BIOPHYSICAL JOURNAL
(2022)
Article
Biophysics
Linda X. Phan, Charlotte Lynch, Jason Crain, Mark S. P. Sansom, Stephen J. Tucker
Summary: Interactions between ions and water at hydrophobic interfaces within ion channels and nanopores are crucial for the movement of ions across biological membranes. Previous molecular-dynamics simulations showed that adding polarization effects can significantly affect the affinity of anions for aqueous/hydrophobic interfaces. Using a model biomimetic nanopore, molecular-dynamics simulations were performed to investigate the behavior of ions and water within the hydrophobic region. The results suggest that effective polarization is essential for an accurate description of ion and water behavior within hydrophobic nanoscale pores, especially for those that conduct Cl-.
BIOPHYSICAL JOURNAL
(2022)
Review
Physiology
David Seiferth, Philip C. Biggin, Stephen J. Tucker
Summary: This article discusses the hydrophobic gating mechanism in ion channels, which regulates ion permeation by controlling the wetness of the pore. The article provides a detailed definition of hydrophobic gating, compares it with other gating mechanisms, and describes the best practices for identifying a hydrophobic gate.
JOURNAL OF GENERAL PHYSIOLOGY
(2022)
Article
Genetics & Heredity
Janina Sormann, Marcus Schewe, Peter Proks, Thibault Jouen-Tachoire, Shanlin Rao, Elena B. Riel, Katherine E. Agre, Amber Begtrup, John Dean, Maria Descartes, Jan Fischer, Alice Gardham, Carrie Lahner, Paul R. Mark, Srikanth Muppidi, Pavel N. Pichurin, Joseph Porrmann, Jens Schallner, Kirstin Smith, Volker Straub, Pradeep Vasudevan, Rebecca Willaert, Elisabeth P. Carpenter, Karin E. J. Rodstrom, Michael G. Hahn, Thomas Mueller, Thomas Baukrowitz, Matthew E. Hurles, Caroline F. Wright, Stephen J. Tucker
Summary: Sleep apnea, a common disorder with significant public health burden, has been associated with rare gain-of-function mutations in the KCNK3 gene, highlighting a new role for TASK-1 K+ channels and presenting possible therapeutic strategies.
Article
Biochemistry & Molecular Biology
Jian Gao, Conor McClenaghan, Imke Christiaans, Marielle Alders, Kirsten van Duinen, Mieke M. van Haelst, Gijs van Haaften, Colin G. Nichols
Summary: Cantu Syndrome is a rare disorder characterized by hypertrichosis, osteochondrodysplasia, and cardiomegaly. A recent study suggests that idiopathic lymphedema may actually be an initial presentation of Cantu Syndrome. Molecular phenotyping is necessary to confirm the relevance of identified variants.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Biophysics
Linda X. Phan, Victor Cruces Chamorro, Hector Martinez-Seara, Jason Crain, Mark S. P. Sansom, Stephen J. Tucker
Summary: In this study, the dynamics of chloride binding to a hydrophobic site in a chloride-pumping rhodopsin were investigated using molecular dynamics simulations. The results demonstrate that the inclusion of polarization leads to stronger ion binding and the formation of a second metastable binding site. The simulations also reveal that chloride interacts with an adjacent loop to facilitate rebinding events when polarization is included.
BIOPHYSICAL JOURNAL
(2023)
Article
Medicine, Research & Experimental
Conor McClenaghan, Maya A. Mukadam, Jacob Roeglin, Robert C. Tryon, Manfred Grabner, Anamika Dayal, Gretchen A. Meyer, Colin G. Nichols
Summary: ABCC9-related intellectual disability and myopathy syndrome (AIMS) is caused by LoF mutations in the ABCC9 gene, leading to dysfunction of SUR2 subunit of K-ATP channels. AIMS individuals experience muscle weakness, spasms, and cardiac dysfunction. The study reveals that myopathy in AIMS is specifically caused by LoF in skeletal muscle, and abnormal unstimulated forces may explain the muscle spasms. The use of calcium channel blockers in AIMS is cautioned against due to unexpected results.
EMBO MOLECULAR MEDICINE
(2023)
Article
Cell Biology
Rosa Scala, Fatima Maqoud, Conor McClenaghan, Theresa M. Harter, Maria Grazia Perrone, Antonio Scilimati, Colin G. Nichols, Domenico Tricarico
Summary: Cantu syndrome is caused by gain of function mutations in the ABCC9 and KCNJ8 genes, resulting in defects in the KATP channels. Glibenclamide has been proposed as a treatment, but it is not effective against certain mutations. Zoledronic acid was found to effectively reduce KATP currents in skeletal muscle and bone cells of Cantu syndrome mice, but not in SUR2 mutant mice. This indicates the importance of subunit specificity for appropriate therapy.
Article
Multidisciplinary Sciences
Yuval Ben-Abu, Stephen J. Tucker, Sonia Contera
Summary: The Markov state model (MSM) is a widely-used theoretical tool for studying time scales in protein function. However, it has limitations when it comes to non-equilibrium situations, such as temperature changes in ion channel gating. In this study, a non-Markovian model is proposed to describe the behavior of temperature-sensitive TRP ion channels, overcoming the limitations of the MSM and providing a better understanding of the underlying physics.
ROYAL SOCIETY OPEN SCIENCE
(2023)
Meeting Abstract
Biophysics
Linda X. Phan, Hector Martinez-Seara, Jason Crain, Mark S. P. Sansom, Stephen J. Tucker
BIOPHYSICAL JOURNAL
(2023)
Meeting Abstract
Biophysics
Stephen J. Tucker
BIOPHYSICAL JOURNAL
(2023)
Article
Chemistry, Physical
David Seiferth, Stephen J. Tucker, Philip C. Biggin
Summary: Transmembrane anion transport by synthetic ionophores is important for understanding endogenous anion transport and has potential therapeutic implications. Computational studies using non-polarizable and polarizable force fields provide insights into the binding properties of anions. The results show solvent dependency and the importance of electrostatics and oxidation status in anion recognition.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2023)
Meeting Abstract
Biophysics
Linda X. Phan, Charlotte I. Lynch, Jason Crain, Mark S. P. Sansom, Stephen J. Tucker
BIOPHYSICAL JOURNAL
(2022)