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PLoS Computational Biology Jun 2024Patients with myocardial ischemia and infarction are at increased risk of arrhythmias, which in turn, can exacerbate the overall risk of mortality. Despite the observed...
Patients with myocardial ischemia and infarction are at increased risk of arrhythmias, which in turn, can exacerbate the overall risk of mortality. Despite the observed reduction in recurrent arrhythmias through antiarrhythmic drug therapy, the precise mechanisms underlying their effectiveness in treating ischemic heart disease remain unclear. Moreover, there is a lack of specialized drugs designed explicitly for the treatment of myocardial ischemic arrhythmia. This study employs an electrophysiological simulation approach to investigate the potential antiarrhythmic effects and underlying mechanisms of various pharmacological agents in the context of ischemia and myocardial infarction (MI). Based on physiological experimental data, computational models are developed to simulate the effects of a series of pharmacological agents (amiodarone, telmisartan, E-4031, chromanol 293B, and glibenclamide) on cellular electrophysiology and utilized to further evaluate their antiarrhythmic effectiveness during ischemia. On 2D and 3D tissues with multiple pathological conditions, the simulation results indicate that the antiarrhythmic effect of glibenclamide is primarily attributed to the suppression of efflux of potassium ion to facilitate the restitution of [K+]o, as opposed to recovery of IKATP during myocardial ischemia. This discovery implies that, during acute cardiac ischemia, pro-arrhythmogenic alterations in cardiac tissue's excitability and conduction properties are more significantly influenced by electrophysiological changes in the depolarization rate, as opposed to variations in the action potential duration (APD). These findings offer specific insights into potentially effective targets for investigating ischemic arrhythmias, providing significant guidance for clinical interventions in acute coronary syndrome.
PubMed: 38917196
DOI: 10.1371/journal.pcbi.1012244 -
Proceedings of the National Academy of... Jul 2024HCN1-4 channels are the molecular determinants of the I/I current that crucially regulates cardiac and neuronal cell excitability. HCN dysfunctions lead to sinoatrial...
HCN1-4 channels are the molecular determinants of the I/I current that crucially regulates cardiac and neuronal cell excitability. HCN dysfunctions lead to sinoatrial block (HCN4), epilepsy (HCN1), and chronic pain (HCN2), widespread medical conditions awaiting subtype-specific treatments. Here, we address the problem by solving the cryo-EM structure of HCN4 in complex with ivabradine, to date the only HCN-specific drug on the market. Our data show ivabradine bound inside the open pore at 3 Å resolution. The structure unambiguously proves that Y507 and I511 on S6 are the molecular determinants of ivabradine binding to the inner cavity, while F510, pointing outside the pore, indirectly contributes to the block by controlling Y507. Cysteine 479, unique to the HCN selectivity filter (SF), accelerates the kinetics of block. Molecular dynamics simulations further reveal that ivabradine blocks the permeating ion inside the SF by electrostatic repulsion, a mechanism previously proposed for quaternary ammonium ions.
Topics: Ivabradine; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Molecular Dynamics Simulation; Humans; Cryoelectron Microscopy; Animals; Potassium Channels; Muscle Proteins
PubMed: 38917012
DOI: 10.1073/pnas.2402259121 -
BioRxiv : the Preprint Server For... Jun 2024The vestibular nerve is comprised of neuron sub-groups with diverse functions related to their intrinsic biophysical properties. This diversity is partly due to...
The vestibular nerve is comprised of neuron sub-groups with diverse functions related to their intrinsic biophysical properties. This diversity is partly due to differences in the types and numbers of low-voltage-gated potassium channels found in the neurons' membranes. Expression for some low-voltage gated ion channels like KCNQ4 is upregulated during early post-natal development; suggesting that ion channel composition and neuronal diversity may be shaped by hair cell activity. This idea is consistent with recent work showing that glutamatergic input from hair cells is necessary for the normal diversification auditory neurons. To test if biophysical diversity is similarly dependent on glutamatergic input in vestibular neurons, we examined the maturation of the vestibular epithelium and ganglion neurons in mice whose hair cell synapses lack glutamate. Despite lacking glutamatergic input, the knockout mice showed no notable balance deficits and crossed challenging balance beams with little difficulty. Immunolabeling of the vestibular epithelia showed normal development as indicated by an identifiable striolar zone with calyceal terminals labeled by molecular marker calretinin, and normal expression of KCNQ4 by the end of the second post-natal week. We found similar numbers of Type I and Type II hair cells in the knockout and wildtype animals, regardless of epithelial zone. Thus, the presumably quiescent Type II hair cells are not cleared from the epithelium. Patch-clamp recordings showed that biophysical diversity of vestibular ganglion neurons in the mice is comparable to that found in wildtype controls, with a similar range firing patterns at both immature and juvenile ages. However, our results suggest a subtle biophysical alteration to the largest ganglion cells (putative somata of central zone afferents); those in the knockout had smaller net conductance and were more excitable than those in the wild type. Thus, unlike in the auditory nerve, glutamatergic signaling is unnecessary for producing biophysical diversity in vestibular ganglion neurons. And yet, because the input signals from vestibular hair cells are complex and not solely reliant on quantal release of glutamate, whether diversity of vestibular ganglion neurons is simply hardwired or regulated by a more complex set of input signals remains to be determined.
PubMed: 38915604
DOI: 10.1101/2024.06.12.597464 -
BioRxiv : the Preprint Server For... Jun 2024Ion channels are essential for proper morphogenesis of the craniofacial skeleton. However, the molecular mechanisms underlying this phenomenon are unknown. Loss of the...
UNLABELLED
Ion channels are essential for proper morphogenesis of the craniofacial skeleton. However, the molecular mechanisms underlying this phenomenon are unknown. Loss of the potassium channel disrupts Bone Morphogenetic Protein (BMP) signaling within the developing palate. BMP signaling is essential for the correct development of several skeletal structures, including the palate, though little is known about the mechanisms that govern BMP secretion. We introduce a tool to image the release of bone morphogenetic protein 4 (BMP4) from mammalian cells. Using this tool, we show that depolarization induces BMP4 release from mouse embryonic palate mesenchyme cells in a calcium-dependent manner. We show native transient changes in intracellular calcium occur in cranial neural crest cells, the cells from which embryonic palate mesenchyme derives. Waves of transient changes in intracellular calcium suggest that these cells are electrically coupled and may temporally coordinate BMP release. These transient changes in intracellular calcium persist in palate mesenchyme cells from embryonic day (E) 9.5 to 13.5 mice. Disruption of significantly decreases the amplitude of calcium transients and the ability of cells to secrete BMP. Together, these data suggest that temporal control of developmental cues is regulated by ion channels, depolarization, and changes in intracellular calcium for mammalian craniofacial morphogenesis.
SUMMARY
We show that embryonic palate mesenchyme cells undergo transient changes in intracellular calcium. Depolarization of these cells induces BMP4 release suggesting that ion channels are a node in BMP4 signaling.
PubMed: 38915514
DOI: 10.1101/2024.06.11.598333 -
Brain Communications 2024While voltage-gated potassium channels have critical roles in controlling neuronal excitability, they also have non-ion-conducting functions. Kv8.1, encoded by the KCNV1...
While voltage-gated potassium channels have critical roles in controlling neuronal excitability, they also have non-ion-conducting functions. Kv8.1, encoded by the KCNV1 gene, is a 'silent' ion channel subunit whose biological role is complex since Kv8.1 subunits do not form functional homotetramers but assemble with Kv2 to modify its ion channel properties. We profiled changes in ion channel expression in amyotrophic lateral sclerosis patient-derived motor neurons carrying a superoxide dismutase 1(A4V) mutation to identify what drives their hyperexcitability. A major change identified was a substantial reduction of KCNV1/Kv8.1 expression, which was also observed in patient-derived neurons with C9orf72 expansion. We then studied the effect of reducing KCNV1/Kv8.1 expression in healthy motor neurons and found it did not change neuronal firing but increased vulnerability to cell death. A transcriptomic analysis revealed dysregulated metabolism and lipid/protein transport pathways in KCNV1/Kv8.1-deficient motor neurons. The increased neuronal vulnerability produced by the loss of KCNV1/Kv8.1 was rescued by knocking down Kv2.2, suggesting a potential Kv2.2-dependent downstream mechanism in cell death. Our study reveals, therefore, unsuspected and distinct roles of Kv8.1 and Kv2.2 in amyotrophic lateral sclerosis-related neurodegeneration.
PubMed: 38911266
DOI: 10.1093/braincomms/fcae202 -
PloS One 2024Bandon Bay is a very fertile bay for coastal aquaculture, especially for blood cockles (Anadara granosa). Its structural pattern supports the flow of nutrients which...
Bandon Bay is a very fertile bay for coastal aquaculture, especially for blood cockles (Anadara granosa). Its structural pattern supports the flow of nutrients which directly sent from many rivers resulted the high production capacity of blood cockle at the top level in the country. Besides organic compounds present in sediment, inorganic substances are essential for growth, survival and shell development of blood cockles. A comparative study of minerals and oxide compounds which accumulated in the sediments at eight stations around the cockle culture area was conducted. These stations are located along the estuaries at Tha Thong, Tha Chang, Phum Riang, and Tapi. The proportion of oxide compounds were determinedusing X-Ray Fluorescence (XRF) technique and minerals were analyzed by Atomic Absorption Spectroscopy (AAS). Results showed that sediment characteristics, oxide composition and the amount of minerals among the stations are different from each other. The sediments of the eastern and the western coasts were characterized as crumble clay and muddy sand, respectively. Twelve types of oxide compounds, namely SiO2, Al2O3, Fe2O3, K2O, Cl, MgO, Na2O, SO3, CaO, TiO2, MnO, P2O5 were found in various quantities, with SiO2, Al2O3, and Fe2O3 were the fundamental minerals ranging from 85.64-90.82%. Tha Thong estuary in the east coast showed highly significant quantities (P<0.05) of potassium, calcium and manganese compared to the other estuaries.
Topics: Geologic Sediments; Thailand; Minerals; Oxides; Bays; Animals; Cardiidae; Aquaculture; Spectrometry, X-Ray Emission; Spectrophotometry, Atomic
PubMed: 38905193
DOI: 10.1371/journal.pone.0305061 -
Frontiers in Physiology 2024Ion channels play a pivotal role in regulating cellular excitability and signal transduction processes. Among the various ion channels, G-protein-coupled inwardly... (Review)
Review
Ion channels play a pivotal role in regulating cellular excitability and signal transduction processes. Among the various ion channels, G-protein-coupled inwardly rectifying potassium (GIRK) channels serve as key mediators of neurotransmission and cellular responses to extracellular signals. GIRK channels are members of the larger family of inwardly-rectifying potassium (Kir) channels. Typically, GIRK channels are activated via the direct binding of G-protein βγ subunits upon the activation of G-protein-coupled receptors (GPCRs). GIRK channel activation requires the presence of the lipid signaling molecule, phosphatidylinositol 4,5-bisphosphate (PIP). GIRK channels are also modulated by endogenous proteins and other molecules, including RGS proteins, cholesterol, and SNX27 as well as exogenous compounds, such as alcohol. In the last decade or so, several groups have developed novel drugs and small molecules, such as ML297, GAT1508 and GiGA1, that activate GIRK channels in a G-protein independent manner. Here, we aim to provide a comprehensive overview focusing on the direct modulation of GIRK channels by G-proteins, PIP, cholesterol, and novel modulatory compounds. These studies offer valuable insights into the underlying molecular mechanisms of channel function, and have potential implications for both basic research and therapeutic development.
PubMed: 38903913
DOI: 10.3389/fphys.2024.1386645 -
Nature Communications Jun 2024DNA binding transcription factors possess the ability to interact with lipid membranes to construct ion-permeable pathways. Herein, we present a thiazole-based DNA...
DNA binding transcription factors possess the ability to interact with lipid membranes to construct ion-permeable pathways. Herein, we present a thiazole-based DNA binding peptide mimic TBP2, which forms transmembrane ion channels, impacting cellular ion concentration and consequently stabilizing G-quadruplex DNA structures. TBP2 self-assembles into nanostructures, e.g., vesicles and nanofibers and facilitates the transportation of Na and K across lipid membranes with high conductance (~0.6 nS). Moreover, TBP2 exhibits increased fluorescence when incorporated into the membrane or in cellular nuclei. Monomeric TBP2 can enter the lipid membrane and localize to the nuclei of cancer cells. The coordinated process of time-dependent membrane or nuclear localization of TBP2, combined with elevated intracellular cation levels and direct G-quadruplex (G4) interaction, synergistically promotes formation and stability of G4 structures, triggering cancer cell death. This study introduces a platform to mimic and control intricate biological functions, leading to the discovery of innovative therapeutic approaches.
Topics: Humans; Peptidomimetics; DNA; G-Quadruplexes; Potassium; Cell Line, Tumor; Sodium; Cell Nucleus; Ion Channels; DNA-Binding Proteins
PubMed: 38902227
DOI: 10.1038/s41467-024-49534-0 -
The Journal of Physical Chemistry. C,... Jun 2024Zeolites contain extraframework cations that are exchangeable under favorable aqueous conditions; this is the fundamental feature for their application in water...
Zeolites contain extraframework cations that are exchangeable under favorable aqueous conditions; this is the fundamental feature for their application in water purification and necessary to produce cation forms for other applications such as catalysis. Optimization of the process is common, but there is little fundamental understanding based on real-time experiments of the mechanism of exchange for most zeolites. The sodium and potassium forms of zeolite chabazite selectively uptake Cs by ion exchange, leading to its application in removing radioactive Cs from industrial nuclear waste streams, as well as from contaminated environments in the aftermath of the Fukushima and Three Mile Island accidents. In this study, synchrotron powder X-ray diffraction patterns have been collected on chabazite as it undergoes Cs-ion exchange. Applying Rietveld refinement to these patterns has revealed the time-resolved structural changes that occur in the zeolite as exchange progresses, charting the changes in the spatial distribution of the extraframework cations and water molecules in the structure during the reaction. Ultimately, a detailed mechanistic understanding of how this dynamic ion-exchange reaction occurs has been obtained.
PubMed: 38894753
DOI: 10.1021/acs.jpcc.4c02145 -
Molecules (Basel, Switzerland) May 2024Gain-of-function mutations in the gene, which encodes the sodium-activated potassium channel known as SLACK, are associated with the rare but devastating developmental...
Gain-of-function mutations in the gene, which encodes the sodium-activated potassium channel known as SLACK, are associated with the rare but devastating developmental and epileptic encephalopathy known as epilepsy of infancy with migrating focal seizures (EIMFS). The design of small molecule inhibitors of SLACK channels represents a potential therapeutic approach to the treatment of EIMFS, other childhood epilepsies, and developmental disorders. Herein, we describe a hit optimization effort centered on a xanthine SLACK inhibitor () discovered via a high-throughput screen. Across three distinct regions of the chemotype, we synthesized 58 new analogs and tested each one in a whole-cell automated patch-clamp assay to develop structure-activity relationships for inhibition of SLACK channels. We further evaluated selected analogs for their selectivity versus a variety of other ion channels and for their activity versus clinically relevant SLACK mutants. Selectivity within the series was quite good, including versus hERG. Analog (VU0948578) was a potent inhibitor of WT, A934T, and G288S SLACK, with IC values between 0.59 and 0.71 µM across these variants. VU0948578 represents a useful in vitro tool compound from a chemotype that is distinct from previously reported small molecule inhibitors of SLACK channels.
Topics: Structure-Activity Relationship; Humans; Potassium Channel Blockers; Potassium Channels, Sodium-Activated; Nerve Tissue Proteins; Xanthine; Patch-Clamp Techniques; HEK293 Cells; Molecular Structure; Xanthines
PubMed: 38893312
DOI: 10.3390/molecules29112437