25,203 results match your criteria channel gating

Calcium-Activated K Channels (KCa) and Therapeutic Implications.

Handb Exp Pharmacol 2021 May 5. Epub 2021 May 5.

Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Ireland.

Potassium channels are the most diverse and ubiquitous family of ion channels found in cells. The Ca and voltage gated members form a subfamily that play a variety of roles in both excitable and non-excitable cells and are further classified on the basis of their single channel conductance to form the small conductance (SK), intermediate conductance (IK) and big conductance (BK) K channels.In this chapter, we will focus on the mechanisms underlying the gating of BK channels, whose function is modified in different tissues by different splice variants as well as the expanding array of regulatory accessory subunits including β, γ and LINGO subunits. Read More

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The voltage sensor is responsible for ΔpH dependence in H1 channels.

Proc Natl Acad Sci U S A 2021 May;118(19)

Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, 2351319 Valparaíso, Chile;

The dissipation of acute acid loads by the voltage-gated proton channel (H1) relies on regulating the channel's open probability by the voltage and the ΔpH across the membrane (ΔpH = pH - pH). Using monomeric -H1, we asked whether ΔpH-dependent gating is produced during the voltage sensor activation or permeation pathway opening. A leftward shift of the conductance-voltage (G-V) curve was produced at higher ΔpH values in the monomeric channel. Read More

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PIP regulation of TRPC5 channel activation and desensitization.

J Biol Chem 2021 Apr 29:100726. Epub 2021 Apr 29.

Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences; Center for Drug Discovery; Department of Chemistry and Chemical Biology, College of Science, Northeastern University, Boston, MA. Electronic address:

Transient receptor potential canonical type 5 (TRPC5) ion channels are expressed in the brain and kidney, and have been identified as promising therapeutic targets whose selective inhibition can protect against diseases driven by a leaky kidney filter, such as Focal Segmental Glomerular Sclerosis (FSGS). TRPC5 channels are activated by elevated levels of extracellular Caor lanthanide ions, but also by G protein (G) stimulation. Phosphatidylinositol bisphosphate (PIP) hydrolysis by phospholipase C (PLC) enzymes leads to protein kinase C (PKC)-mediated phosphorylation of TRPC5 channels and their subsequent desensitization. Read More

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Complexity and Specificity of Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61 Complex.

Cells 2021 Apr 27;10(5). Epub 2021 Apr 27.

Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany.

The rough endoplasmic reticulum (ER) of nucleated human cells has crucial functions in protein biogenesis, calcium (Ca) homeostasis, and signal transduction. Among the roughly one hundred components, which are involved in protein import and protein folding or assembly, two components stand out: The Sec61 complex and BiP. The Sec61 complex in the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER and provides a conduit for Ca ions from the ER lumen to the cytosol. Read More

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Differential Regulation of Ca-Activated Cl Channel TMEM16A Splice Variants by Membrane PI(4,5)P.

Int J Mol Sci 2021 Apr 15;22(8). Epub 2021 Apr 15.

Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea.

TMEM16A is a Ca-activated Cl channel that controls broad cellular processes ranging from mucus secretion to signal transduction and neuronal excitability. Recent studies have reported that membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P) is an important cofactor that allosterically regulates TMEM16A channel activity. However, the detailed regulatory actions of PIP in splice variants of TMEM16A remain unclear. Read More

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Effective Activation of BK Channels by QO-40 (5-(Chloromethyl)-3-(Naphthalen-1-yl)-2-(Trifluoromethyl)Pyrazolo [1,5-a]pyrimidin-7(4)-one), Known to Be an Opener of KCNQ2/Q3 Channels.

Pharmaceuticals (Basel) 2021 Apr 21;14(5). Epub 2021 Apr 21.

Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan.

QO-40 (5-(chloromethyl)-3-(naphthalene-1-yl)-2-(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7(4)-one) is a novel and selective activator of KCNQ2/KCNQ3 K channels. However, it remains largely unknown whether this compound can modify any other type of plasmalemmal ionic channel. The effects of QO-40 on ion channels in pituitary GH lactotrophs were investigated in this study. Read More

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The structure of MgtE in the absence of magnesium provides new insights into channel gating.

PLoS Biol 2021 Apr 27;19(4):e3001231. Epub 2021 Apr 27.

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, Shanghai, China.

MgtE is a Mg2+ channel conserved in organisms ranging from prokaryotes to eukaryotes, including humans, and plays an important role in Mg2+ homeostasis. The previously determined MgtE structures in the Mg2+-bound, closed-state, and structure-based functional analyses of MgtE revealed that the binding of Mg2+ ions to the MgtE cytoplasmic domain induces channel inactivation to maintain Mg2+ homeostasis. There are no structures of the transmembrane (TM) domain for MgtE in Mg2+-free conditions, and the pore-opening mechanism has thus remained unclear. Read More

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A conserved residue in the P2X4 receptor has a non-conserved function in ATP recognition.

J Biol Chem 2021 Apr 23:100655. Epub 2021 Apr 23.

School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China;. Electronic address:

Highly conserved amino acids are generally anticipated to have similar functions across a protein superfamily, including that of the P2X ion channels, which are gated by extracellular ATP. However, whether and how these functions are conserved becomes less clear when neighboring amino acids are not conserved. Here, we investigate one such case, focused on the highly conserved residue from P2X4, E118 (rat P2X4 numbering, rP2X4), a P2X subtype associated with human neuropathic pain. Read More

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Insights into the Molecular Inhibition of the Oncogenic Channel K10.1 by Globular Toxins.

J Chem Inf Model 2021 Apr 26. Epub 2021 Apr 26.

Instituto de Ciencias Físicas, Universidad Nacional Autónoma de México, Cuernavaca 62210, Morelos, México.

Inhibition of the expression of the human ether-à-go-go (hEAG1 or hK10.1) channel is associated with a dramatic reduction in the growth of several cancerous tumors. The modulation of this channel's activity is a promising target for the development of new anticancer drugs. Read More

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Analysis of Hemichannels and Gap Junctions: Application and Extension of the Passive Transmembrane Ion Transport Model.

Front Cell Neurosci 2021 7;15:596953. Epub 2021 Apr 7.

School of Mathematics, South China University of Technology, Guangzhou, China.

Electrical synaptic transmission is an essential form of interneuronal communication which is mediated by gap junctions that permit ion flow. Three gene families (connexins, innexins, and pannexins) have evolved to form gap junctional channels. Each gap junctional channel is formed by the docking of the hemichannel of one cell with the corresponding hemichannel of an adjacent cell. Read More

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Structural insights into the mechanisms and pharmacology of K potassium channels.

J Mol Biol 2021 Apr 19:166995. Epub 2021 Apr 19.

Cardiovascular Research Institute; Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology; California Institute for Quantitative Biomedical Research; Kavli Institute for Fundamental Neuroscience University of California, San Francisco, California 93858-2330 USA; Molecular Biophysics and Integrated Bio-imaging Division Lawrence Berkeley National Laboratory, Berkeley, CA 94720 USA. Electronic address:

Leak currents, defined as voltage and time independent flows of ions across cell membranes, are central to cellular electrical excitability control. The K (KCNK) potassium channel class comprises an ion channel family that produces potassium leak currents that oppose excitation and stabilize the resting membrane potential in cells in the brain, cardiovascular system, immune system, and sensory organs. Due to their widespread tissue distribution, Ks contribute to many physiological and pathophysiological processes including anesthesia, pain, arrythmias, ischemia, hypertension, migraine, intraocular pressure regulation, and lung injury responses. Read More

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Asymmetric CorA Gating Mechanism as Observed by Molecular Dynamics Simulations.

J Chem Inf Model 2021 Apr 22. Epub 2021 Apr 22.

Groningen Institute for Biomolecular Sciences and Biotechnology, University of Groningen, 9747AG Groningen, The Netherlands.

The CorA family of proteins plays a housekeeping role in the homeostasis of divalent metal ions in many bacteria and archaea as well as in mitochondria of eukaryotes, rendering it an important target to study the mechanisms of divalent transport and regulation across different life domains. Despite numerous studies, the mechanistic details of the channel gating and the transport of the metal ions are still not entirely understood. Here, we use all-atom and coarse-grained molecular dynamics simulations combined with experiments to investigate the influence of divalent cations on the function of CorA. Read More

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Slow recovery from the inactivation of voltage-gated sodium channel Nav1.3 in mouse taste receptor cells.

Yoshitaka Ohtubo

Pflugers Arch 2021 Apr 21. Epub 2021 Apr 21.

Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Hibikino 2-4, Kitakyushu, 808-0196, Japan.

Action potentials play an important role in neurotransmitter release in response to taste. Here, I have investigated voltage-gated Na channels, a primary component of action potentials, in respective cell types of mouse fungiform taste bud cells (TBCs) with in situ whole-cell clamping and single-cell RT-PCR techniques. The cell types of TBCs electrophysiologically examined were determined immunohistochemically using the type III inositol 1,4,5-triphoshate receptor as a type II cell marker and synaptosomal-associated protein 25 as a type III cell marker. Read More

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The Pharmacology of Two-Pore Domain Potassium Channels.

Handb Exp Pharmacol 2021 Apr 21. Epub 2021 Apr 21.

Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.

Two-pore domain potassium channels are formed by subunits that each contain two pore-loops moieties. Whether the channels are expressed in yeast or the human central nervous system, two subunits come together to form a single potassium selective pore. TOK1, the first two-domain channel was cloned from Saccharomyces cerevisiae in 1995 and soon thereafter, 15 distinct K subunits were identified in the human genome. Read More

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More Than Just Closed and Open: Unraveling a Mechanosensor.

Trends Biochem Sci 2021 Apr 17. Epub 2021 Apr 17.

Biocenter and Rudolf-Virchow-Zentrum, Universität Würzburg, Haus D15, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. Electronic address:

The bacterial mechanosensitive channel of small conductance (MscS) is a well-studied model of how mechanical forces from the membrane can be sensed by an embedded protein. A recent study by Zhang et al. visualizes how MscS behaves under membrane tension, entering a desensitized state when it loses all coordinated lipids. Read More

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Enhancement of in vivo cardiac photoacoustic signal specificity using spatiotemporal singular value decomposition.

J Biomed Opt 2021 Apr;26(4)

University of Wisconsin-Madison, Department of ECE, Madison, Wisconsin, United States.

Significance: Photoacoustic imaging (PAI) can be used to infer molecular information about myocardial health non-invasively in vivo using optical excitation at ultrasonic spatial resolution. For clinical and preclinical linear array imaging systems, conventional delay-and-sum (DAS) beamforming is typically used. However, DAS cardiac PA images are prone to artifacts such as diffuse quasi-static clutter with temporally varying noise-reducing myocardial signal specificity. Read More

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Connexin 46 and connexin 50 gap junction channel properties are shaped by structural and dynamic features of their N-terminal domains.

J Physiol 2021 Apr 20. Epub 2021 Apr 20.

Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.

Key Points: Gap junctions formed by different connexins are expressed throughout the body and harbor unique channel properties that have not been fully defined mechanistically. Recent structural studies by Cryo-EM have produced high-resolution models of the related but functionally distinct lens connexins (Cx50 and Cx46) captured in a stable open state, opening the door for structure-function comparison. Here, we conducted comparative MD simulation and electrophysiology studies to dissect the isoform-specific differences in Cx46 and Cx50 intercellular channel function. Read More

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On the molecular nature of large-pore channels.

J Mol Biol 2021 Apr 16:166994. Epub 2021 Apr 16.

W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:

Membrane transport is a fundamental means to control basic cellular processes such as apoptosis, inflammation, and neurodegeneration and is mediated by a number of transporters, pumps, and channels. Accumulating evidence over the last half century has shown that a type of so-called "large-pore channel" exists in various tissues and organs in gap-junctional and non-gap-junctional forms in order to flow not only ions but also metabolites such as ATP. They are formed by a number of protein families with little or no evolutionary linkages including connexin, innexin, pannexin, leucine-rich repeat-containing 8 (LRRC8), and calcium homeostasis modulator (CALHM). Read More

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An arginine residue in the outer segment of hASIC1a TM1 affects both proton affinity and channel desensitization.

J Gen Physiol 2021 May;153(5)

Department of Basic Sciences, Tsinghua University School of Medicine, Beijing, China.

Acid-sensing ion channels (ASICs) respond to changes in pH in the central and peripheral nervous systems and participate in synaptic plasticity and pain perception. Understanding the proton-mediated gating mechanism remains elusive despite the of their structures in various conformational states. We report here that R64, an arginine located in the outer segment of the first transmembrane domain of all three isoforms of mammalian ASICs, markedly impacts the apparent proton affinity of activation and the degree of desensitization from the open and preopen states. Read More

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Extracellular cap domain is an essential component of the TRPV1 gating mechanism.

Nat Commun 2021 04 12;12(1):2154. Epub 2021 Apr 12.

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.

Transient receptor potential (TRP) channels are polymodal molecular sensors involved in numerous physiological processes and implicated in a variety of human diseases. Several structures of the founding member of the TRP channel family, TRPV1, are available, all of which were determined for the protein missing the N- and C-termini and the extracellular S5-P-loop. Here, we present structures of the full-length thirteen-lined ground squirrel TRPV1 solved by cryo-EM. Read More

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A Light-Operated Molecular Cable Car for Gated Ion Transport.

Angew Chem Int Ed Engl 2021 Apr 11. Epub 2021 Apr 11.

Key Labs for Advanced Materials, East China University of Science and Technology, CHINA.

Inspired by the nontrivial and controlled movements of molecular machines, we report an azobenzene-based molecular shuttle PR2 , which can perform light-gated ion transport across lipid membranes. The amphiphilicity and membrane-spanned molecular length enable PR2 to insert into the bilayer membrane and efficiently ferry K + (EC 50 = 4.1 µM) through the thermally driven stochastic shuttle motion of the crown ether ring along the axle. Read More

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High-Resolution Structures of K Channels.

Qiu-Xing Jiang

Handb Exp Pharmacol 2021 Apr 8. Epub 2021 Apr 8.

Laboratory of Molecular Physiology and Biophysics and the Cryo-EM Center, Hauptmann-Woodward Medical Research Institute, Buffalo, NY, USA.

Potassium channels are present in every living cell and essential to setting up a stable, non-zero transmembrane electrostatic potential which manifests the off-equilibrium livelihood of the cell. They are involved in other cellular activities and regulation, such as the controlled release of hormones, the activation of T-cells for immune response, the firing of action potential in muscle cells and neurons, etc. Pharmacological reagents targeting potassium channels are important for treating various human diseases linked to dysfunction of the channels. Read More

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A Heart Failure-Associated Splice Variant Leads to a Reduction in Sodium Current Through Coupled-Gating With the Wild-Type Channel.

Front Physiol 2021 22;12:661429. Epub 2021 Mar 22.

Department of Physiology and Cell Biology, Frick Center for Heart Failure and Arrhythmias, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, United States.

Na1.5, encoded by the gene , is the predominant voltage-gated sodium channel expressed in the heart. It initiates the cardiac action potential and thus is crucial for normal heart rhythm and function. Read More

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Differential sensitivity of cinnamaldehyde-evoked calcium fluxes to ruthenium red in guinea pig and mouse trigeminal sensory neurons.

BMC Res Notes 2021 Apr 7;14(1):127. Epub 2021 Apr 7.

Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL, 33612, USA.

Objective: Transient receptor potential ankyrin 1 (TRPA1) is an excitatory ion channel expressed on a subset of sensory neurons. TRPA1 is activated by a host of noxious stimuli including pollutants, irritants, oxidative stress and inflammation, and is thought to play an important role in nociception and pain perception. TRPA1 is therefore a therapeutic target for diseases with nociceptive sensory signaling components. Read More

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Kir4.1/Kir5.1 channels possess strong intrinsic inward rectification determined by a voltage-dependent K+-flux gating mechanism.

J Gen Physiol 2021 May;153(5)

Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México.

Inwardly rectifying potassium (Kir) channels are broadly expressed in both excitable and nonexcitable tissues, where they contribute to a wide variety of cellular functions. Numerous studies have established that rectification of Kir channels is not an inherent property of the channel protein itself, but rather reflects strong voltage dependence of channel block by intracellular cations, such as polyamines and Mg2+. Here, we identify a previously unknown mechanism of inward rectification in Kir4. Read More

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Unmasking coupling between channel gating and ion permeation in the muscle nicotinic receptor.

Elife 2021 04 6;10. Epub 2021 Apr 6.

Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Rochester, United States.

Whether ion channel gating is independent of ion permeation has been an enduring, unresolved question. Here, applying single channel recording to the archetypal muscle nicotinic receptor, we unmask coupling between channel gating and ion permeation by structural perturbation of a conserved intramembrane salt bridge. A charge-neutralizing mutation suppresses channel gating, reduces unitary current amplitude, and increases fluctuations of the open channel current. Read More

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Probing the physiological roles of the extracellular loops of chitoporin from Vibrio campbellii.

Biophys J 2021 Apr 1. Epub 2021 Apr 1.

School of Biomolecular Science and Engineering (BSE), Vidyasirimedhi Institute of Science and Technology (VISTEC), Rayong, Thailand. Electronic address:

VhChiP, a sugar-specific porin found on the outer membrane of Vibrio campbellii, is responsible for the transport of chitooligosaccharides, allowing the bacterium to thrive in aquatic environments using chitin as a nutrient. We previously showed that VhChiP is composed of three identical subunits, each containing a 16-stranded β-barrel connected by eight extracellular loops and eight short periplasmic turns. This study is focused on the specific roles of three prominent extracellular loops of VhChiP-L2, L3, and L8. Read More

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The Open State Selectivity of the Bean Seed VDAC Depends on Stigmasterol and Ion Concentration.

Int J Mol Sci 2021 Mar 16;22(6). Epub 2021 Mar 16.

Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles (ULB), Boulevard du Triomphe CP 206/2, B-1050 Bruxelles, Belgium.

The voltage-dependent anion channel (VDAC) is the major pathway for metabolites and ions transport through the mitochondrial outer membrane. It can regulate the flow of solutes by switching to a low conductance state correlated with a selectivity reversal, or by a selectivity inversion of its open state. The later one was observed in non-plant VDACs and is poorly characterized. Read More

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3D Pharmacophore-Based Discovery of Novel K10.1 Inhibitors with Antiproliferative Activity.

Cancers (Basel) 2021 Mar 12;13(6). Epub 2021 Mar 12.

Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.

(1) Background: The voltage-gated potassium channel K10.1 (Eag1) is considered a near- universal tumour marker and represents a promising new target for the discovery of novel anticancer drugs. (2) Methods: We utilized the ligand-based drug discovery methodology using 3D pharmacophore modelling and medicinal chemistry approaches to prepare a novel structural class of K10. Read More

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Potency-Enhancing Mutations of Gating Modifier Toxins for the Voltage-Gated Sodium Channel Na1.7 Can Be Predicted Using Accurate Free-Energy Calculations.

Toxins (Basel) 2021 Mar 7;13(3). Epub 2021 Mar 7.

Schrӧdinger, Inc., 120 West 45th St., New York, NY 10036, USA.

Gating modifier toxins (GMTs) isolated from venomous organisms such as Protoxin-II (ProTx-II) and Huwentoxin-IV (HwTx-IV) that inhibit the voltage-gated sodium channel Na1.7 by binding to its voltage-sensing domain II (VSDII) have been extensively investigated as non-opioid analgesics. However, reliably predicting how a mutation to a GMT will affect its potency for Na1. Read More

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