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Channels (Austin, Tex.) Jul 2017
Topics: Glycosylation; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Large-Conductance Calcium-Activated Potassium Channel beta Subunits; Large-Conductance Calcium-Activated Potassium Channels; Phenotype; Spices; Sugars
PubMed: 28118079
DOI: 10.1080/19336950.2017.1286829 -
Cardiac Electrophysiology Clinics Jun 2016Human cardiomyocytes express 3 distinct types of delayed rectifier potassium channels. Human ether-a-go-go-related gene (hERG) channels conduct the rapidly activating... (Review)
Review
Human cardiomyocytes express 3 distinct types of delayed rectifier potassium channels. Human ether-a-go-go-related gene (hERG) channels conduct the rapidly activating current IKr; KCNQ1/KCNE1 channels conduct the slowly activating current IKs; and Kv1.5 channels conduct an ultrarapid activating current IKur. Here the authors provide a general overview of the mechanistic and structural basis of ion selectivity, gating, and pharmacology of the 3 types of cardiac delayed rectifier potassium ion channels. Most blockers bind to S6 residues that line the central cavity of the channel, whereas activators interact with the channel at 4 symmetric binding sites outside the cavity.
Topics: Delayed Rectifier Potassium Channels; Humans; Models, Molecular; Mutation; Potassium Channel Blockers
PubMed: 27261821
DOI: 10.1016/j.ccep.2016.01.002 -
Physiology (Bethesda, Md.) Jan 2023Potassium channels are widespread over all kingdoms and play an important role in the maintenance of cellular ionic homeostasis. Kv1.3 is a voltage-gated potassium... (Review)
Review
Potassium channels are widespread over all kingdoms and play an important role in the maintenance of cellular ionic homeostasis. Kv1.3 is a voltage-gated potassium channel of the Shaker family with a wide tissue expression and a well-defined pharmacology. In recent decades, experiments mainly based on pharmacological modulation of Kv1.3 have highlighted its crucial contribution to different fundamental processes such as regulation of proliferation, apoptosis, and metabolism. These findings link channel function to various pathologies ranging from autoimmune diseases to obesity and cancer. In the present review, we briefly summarize studies employing Kv1.3 knockout animal models to confirm such roles and discuss the findings in comparison to the results obtained by pharmacological modulation of Kv1.3 in various pathophysiological settings. We also underline how these studies contributed to our understanding of channel function in vivo and propose possible future directions.
Topics: Animals; Potassium Channels, Voltage-Gated; Potassium Channels
PubMed: 35998249
DOI: 10.1152/physiol.00010.2022 -
Journal of Molecular Biology Aug 2021Potassium channels play critical roles in many physiological processes, providing a selective permeation route for K ions in and out of a cell, by employing a carefully... (Review)
Review
Potassium channels play critical roles in many physiological processes, providing a selective permeation route for K ions in and out of a cell, by employing a carefully designed selectivity filter, evolutionarily conserved from viruses to mammals. The structure of the selectivity filter was determined at atomic resolution by x-ray crystallography, showing a tight coordination of desolvated K ions by the channel. However, the molecular mechanism of K ions permeation through potassium channels remains unclear, with structural, functional and computational studies often providing conflicting data and interpretations. In this review, we will present the proposed mechanisms, discuss their origins, and will critically assess them against all available data. General properties shared by all potassium channels are introduced first, followed by the introduction of two main mechanisms of ion permeation: soft and direct knock-on. Then, we will discuss critical computational and experimental studies that shaped the field. We will especially focus on molecular dynamics (MD) simulations, that provided mechanistic and energetic aspects of K permeation, but at the same time created long-standing controversies. Further challenges and possible solutions are presented as well.
Topics: Humans; Ion Channel Gating; Molecular Dynamics Simulation; Permeability; Potassium; Potassium Channels
PubMed: 33891905
DOI: 10.1016/j.jmb.2021.167002 -
Expert Opinion on Therapeutic Targets May 2018Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death.... (Review)
Review
Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable. Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed. The main ion channel/transporter targets for antiarrhythmic pharmacology are considered in respect of potential genotype-specific and non-specific treatments for the syndrome. Expert opinion: Potassium channel blockade is valuable for restoring repolarisation and QT interval, though genotype-specific limitations exist in the use of some K channel inhibitors. A combination of K current inhibition during the action potential plateau, with sodium channel inhibition that collectively result in delaying repolarisation and post-repolarisation refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry. Genotype-specific K channel inhibition is limited by a lack of targeted inhibitors in clinical use, though experimentally available selective inhibitors now exist. The relatively low proportion of successfully genotyped cases justifies an exome or genome sequencing approach, to reveal new mediators and targets, as demonstrated recently for SLC4A3 in SQT8.
Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drug Design; Genotype; Humans; Molecular Targeted Therapy; Potassium Channel Blockers; Potassium Channels; Sodium Channel Blockers
PubMed: 29697308
DOI: 10.1080/14728222.2018.1470621 -
Antioxidants & Redox Signaling Aug 2014Voltage-gated K+ channels are a large family of K+-selective ion channel protein complexes that open on membrane depolarization. These K+ channels are expressed in... (Review)
Review
SIGNIFICANCE
Voltage-gated K+ channels are a large family of K+-selective ion channel protein complexes that open on membrane depolarization. These K+ channels are expressed in diverse tissues and their function is vital for numerous physiological processes, in particular of neurons and muscle cells. Potentially reversible oxidative regulation of voltage-gated K+ channels by reactive species such as reactive oxygen species (ROS) represents a contributing mechanism of normal cellular plasticity and may play important roles in diverse pathologies including neurodegenerative diseases.
RECENT ADVANCES
Studies using various protocols of oxidative modification, site-directed mutagenesis, and structural and kinetic modeling provide a broader phenomenology and emerging mechanistic insights.
CRITICAL ISSUES
Physicochemical mechanisms of the functional consequences of oxidative modifications of voltage-gated K+ channels are only beginning to be revealed. In vivo documentation of oxidative modifications of specific amino-acid residues of various voltage-gated K+ channel proteins, including the target specificity issue, is largely absent.
FUTURE DIRECTIONS
High-resolution chemical and proteomic analysis of ion channel proteins with respect to oxidative modification combined with ongoing studies on channel structure and function will provide a better understanding of how the function of voltage-gated K+ channels is tuned by ROS and the corresponding reducing enzymes to meet cellular needs.
Topics: Animals; Ether-A-Go-Go Potassium Channels; Humans; KCNQ Potassium Channels; Large-Conductance Calcium-Activated Potassium Channels; Multigene Family; Oxidation-Reduction; Potassium Channels, Voltage-Gated
PubMed: 24040918
DOI: 10.1089/ars.2013.5614 -
Proceedings of the National Academy of... Apr 2022We report on a heterozygous KCNA2 variant in a child with epilepsy. KCNA2 encodes KV1.2 subunits, which form homotetrameric potassium channels and participate in...
We report on a heterozygous KCNA2 variant in a child with epilepsy. KCNA2 encodes KV1.2 subunits, which form homotetrameric potassium channels and participate in heterotetrameric channel complexes with other KV1-family subunits, regulating neuronal excitability. The mutation causes substitution F233S at the KV1.2 charge transfer center of the voltage-sensing domain. Immunocytochemical trafficking assays showed that KV1.2(F233S) subunits are trafficking deficient and reduce the surface expression of wild-type KV1.2 and KV1.4: a dominant-negative phenotype extending beyond KCNA2, likely profoundly perturbing electrical signaling. Yet some KV1.2(F233S) trafficking was rescued by wild-type KV1.2 and KV1.4 subunits, likely in permissible heterotetrameric stoichiometries: electrophysiological studies utilizing applied transcriptomics and concatemer constructs support that up to one or two KV1.2(F233S) subunits can participate in trafficking-capable heterotetramers with wild-type KV1.2 or KV1.4, respectively, and that both early and late events along the biosynthesis and secretion pathway impair trafficking. These studies suggested that F233S causes a depolarizing shift of ∼48 mV on KV1.2 voltage dependence. Optical tracking of the KV1.2(F233S) voltage-sensing domain (rescued by wild-type KV1.2 or KV1.4) revealed that it operates with modestly perturbed voltage dependence and retains pore coupling, evidenced by off-charge immobilization. The equivalent mutation in the Shaker K+ channel (F290S) was reported to modestly affect trafficking and strongly affect function: an ∼80-mV depolarizing shift, disrupted voltage sensor activation and pore coupling. Our work exposes the multigenic, molecular etiology of a variant associated with epilepsy and reveals that charge-transfer-center disruption has different effects in KV1.2 and Shaker, the archetypes for potassium channel structure and function.
Topics: Cell Membrane; Child; Epilepsy; Humans; Kv1.1 Potassium Channel; Kv1.2 Potassium Channel; Mutation; Potassium; Potassium Channels
PubMed: 35439054
DOI: 10.1073/pnas.2113675119 -
Molecules (Basel, Switzerland) May 2019Scorpion toxins are well-known as the largest potassium channel peptide blocker family. They have been successfully proven to be valuable molecular probes for structural... (Review)
Review
Scorpion toxins are well-known as the largest potassium channel peptide blocker family. They have been successfully proven to be valuable molecular probes for structural research on diverse potassium channels. The potassium channel pore region, including the turret and filter regions, is the binding interface for scorpion toxins, and structural features from different potassium channels have been identified using different scorpion toxins. According to the spatial orientation of channel turrets with differential sequence lengths and identities, conformational changes and molecular surface properties, the potassium channel turrets can be divided into the following three states: open state with less hindering effects on toxin binding, half-open state or half-closed state with certain effects on toxin binding, and closed state with remarkable effects on toxin binding. In this review, we summarized the diverse structural features of potassium channels explored using scorpion toxin tools and discuss future work in the field of scorpion toxin-potassium channel interactions.
Topics: Amino Acid Sequence; Animals; Binding Sites; Humans; Models, Molecular; Molecular Conformation; Molecular Probes; Potassium Channel Blockers; Potassium Channels; Protein Binding; Scorpion Venoms; Scorpions; Structure-Activity Relationship
PubMed: 31146335
DOI: 10.3390/molecules24112045 -
Channels (Austin, Tex.) 2018Potassium currents determine the resting membrane potential and govern repolarisation in cardiac myocytes. Here, we review the various currents in the sinoatrial node... (Review)
Review
Potassium currents determine the resting membrane potential and govern repolarisation in cardiac myocytes. Here, we review the various currents in the sinoatrial node focussing on their molecular and cellular properties and their role in pacemaking and heart rate control. We also describe how our recent finding of a novel ATP-sensitive potassium channel population in these cells fits into this picture.
Topics: Animals; Heart Rate; Humans; Potassium Channels; Sinoatrial Node
PubMed: 30301404
DOI: 10.1080/19336950.2018.1532255 -
Biochimica Et Biophysica Acta.... Nov 2022KCNQ1 (Kv7.1 or KvLQT1) is a voltage-gated potassium ion channel that is involved in the ventricular repolarization following an action potential in the heart. It forms...
KCNQ1 (Kv7.1 or KvLQT1) is a voltage-gated potassium ion channel that is involved in the ventricular repolarization following an action potential in the heart. It forms a complex with KCNE1 in the heart and is the pore forming subunit of slow delayed rectifier potassium current (I). Mutations in KCNQ1, leading to a dysfunctional channel or loss of activity have been implicated in a cardiac disorder, long QT syndrome. In this study, we report the overexpression, purification, biochemical characterization of human KCNQ1, and lipid bilayer dynamics upon interaction with KCNQ1. The recombinant human KCNQ1 was expressed in Escherichia coli and purified into n-dodecylphosphocholine (DPC) micelles. The purified KCNQ1 was biochemically characterized by SDS-PAGE electrophoresis, western blot and nano-LC-MS/MS to confirm the identity of the protein. Circular dichroism (CD) spectroscopy was utilized to confirm the secondary structure of purified protein in vesicles. Furthermore, P and H solid-state NMR spectroscopy in DPPC/POPC/POPG vesicles (MLVs) indicated a direct interaction between KCNQ and the phospholipid head groups. Finally, a visual inspection of KCNQ1 incorporated into MLVs was confirmed by transmission electron microscopy (TEM). The findings of this study provide avenues for future structural studies of the human KCNQ1 ion channel to have an in depth understanding of its structure-function relationship.
Topics: Humans; KCNQ1 Potassium Channel; Long QT Syndrome; Potassium; Potassium Channels; Potassium Channels, Voltage-Gated; Tandem Mass Spectrometry
PubMed: 35870481
DOI: 10.1016/j.bbamem.2022.184010