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Cell Jan 2020KCNQ1, also known as Kv7.1, is a voltage-dependent K channel that regulates gastric acid secretion, salt and glucose homeostasis, and heart rhythm. Its functional...
KCNQ1, also known as Kv7.1, is a voltage-dependent K channel that regulates gastric acid secretion, salt and glucose homeostasis, and heart rhythm. Its functional properties are regulated in a tissue-specific manner through co-assembly with beta subunits KCNE1-5. In non-excitable cells, KCNQ1 forms a complex with KCNE3, which suppresses channel closure at negative membrane voltages that otherwise would close it. Pore opening is regulated by the signaling lipid PIP2. Using cryoelectron microscopy (cryo-EM), we show that KCNE3 tucks its single-membrane-spanning helix against KCNQ1, at a location that appears to lock the voltage sensor in its depolarized conformation. Without PIP2, the pore remains closed. Upon addition, PIP2 occupies a site on KCNQ1 within the inner membrane leaflet, which triggers a large conformational change that leads to dilation of the pore's gate. It is likely that this mechanism of PIP2 activation is conserved among Kv7 channels.
Topics: Cryoelectron Microscopy; Humans; Ion Channel Gating; KCNQ1 Potassium Channel; Membrane Potentials; Patch-Clamp Techniques; Phosphatidylinositol 4,5-Diphosphate; Potassium Channels, Voltage-Gated
PubMed: 31883792
DOI: 10.1016/j.cell.2019.12.003 -
Human Mutation Jan 2020Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently... (Review)
Review
Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage-dependent potassium channel K 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of K 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less-severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.
Topics: Alleles; Epilepsy; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Neurodevelopmental Disorders; Phenotype; Shab Potassium Channels; Structure-Activity Relationship
PubMed: 31513310
DOI: 10.1002/humu.23915 -
Nature Communications Jun 2023Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including...
Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.
Topics: Animals; Mice; Epilepsy; KCNQ Potassium Channels; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Neurons; Seizures
PubMed: 37321992
DOI: 10.1038/s41467-023-39203-z -
Biomolecules Aug 2020Mitochondrial potassium channels have been described as important factors in cell pro-life and death phenomena. The activation of mitochondrial potassium channels, such... (Review)
Review
Mitochondrial potassium channels have been described as important factors in cell pro-life and death phenomena. The activation of mitochondrial potassium channels, such as ATP-regulated or calcium-activated large conductance potassium channels, may have cytoprotective effects in cardiac or neuronal tissue. It has also been shown that inhibition of the mitochondrial Kv1.3 channel may lead to cancer cell death. Hence, in this paper, we examine the concept of the druggability of mitochondrial potassium channels. To what extent are mitochondrial potassium channels an important, novel, and promising drug target in various organs and tissues? The druggability of mitochondrial potassium channels will be discussed within the context of channel molecular identity, the specificity of potassium channel openers and inhibitors, and the unique regulatory properties of mitochondrial potassium channels. Future prospects of the druggability concept of mitochondrial potassium channels will be evaluated in this paper.
Topics: Animals; Drug Design; Humans; Mitochondria; Molecular Targeted Therapy; Potassium Channels
PubMed: 32824877
DOI: 10.3390/biom10081200 -
Molecules (Basel, Switzerland) Jan 2023The Ca ion is used ubiquitously as an intracellular signaling molecule due to its high external and low internal concentration. Many Ca-sensing ion channel proteins have... (Review)
Review
The Ca ion is used ubiquitously as an intracellular signaling molecule due to its high external and low internal concentration. Many Ca-sensing ion channel proteins have evolved to receive and propagate Ca signals. Among them are the Ca-activated potassium channels, a large family of potassium channels activated by rises in cytosolic calcium in response to Ca influx via Ca-permeable channels that open during the action potential or Ca release from the endoplasmic reticulum. The Ca sensitivity of these channels allows internal Ca to regulate the electrical activity of the cell membrane. Activating these potassium channels controls many physiological processes, from the firing properties of neurons to the control of transmitter release. This review will discuss what is understood about the Ca sensitivity of the two best-studied groups of Ca-sensitive potassium channels: large-conductance Ca-activated K channels, K1.1, and small/intermediate-conductance Ca-activated K channels, K2.x/K3.1.
Topics: Potassium Channels; Intermediate-Conductance Calcium-Activated Potassium Channels; Small-Conductance Calcium-Activated Potassium Channels; Cell Membrane; Membrane Potentials; Calcium; Potassium
PubMed: 36677942
DOI: 10.3390/molecules28020885 -
The International Journal of... Aug 2020In this review, we describe key signaling pathways regulating potassium channels present in the inner mitochondrial membrane. The signaling cascades covered here include... (Review)
Review
In this review, we describe key signaling pathways regulating potassium channels present in the inner mitochondrial membrane. The signaling cascades covered here include phosphorylation, redox reactions, modulation by calcium ions and nucleotides. The following types of potassium channels have been identified in the inner mitochondrial membrane of various tissues: ATP-sensitive, Ca-activated, voltage-gated and two-pore domain potassium channels. The direct roles of these channels involve regulation of mitochondrial respiration, membrane potential and synthesis of reactive oxygen species (ROS). Changes in channel activity lead to diverse pro-life and pro-death responses in different cell types. Hence, characterizing the signaling pathways regulating mitochondrial potassium channels will facilitate understanding the physiological role of these proteins. Additionally, we describe in this paper certain regulatory mechanisms, which are unique to mitochondrial potassium channels.
Topics: Adenosine Triphosphate; Animals; Calcium; Humans; Mitochondria; Mitochondrial Membranes; Oxidation-Reduction; Potassium Channels; Potassium Channels, Calcium-Activated; Potassium Channels, Tandem Pore Domain; Potassium Channels, Voltage-Gated; Reactive Oxygen Species; Signal Transduction
PubMed: 32574707
DOI: 10.1016/j.biocel.2020.105792 -
Epilepsia Oct 2022Voltage-gated sodium and potassium channels regulate the initiation and termination of neuronal action potentials. Gain-of-function mutations of sodium channel Scn8a and...
Voltage-gated sodium and potassium channels regulate the initiation and termination of neuronal action potentials. Gain-of-function mutations of sodium channel Scn8a and loss-of-function mutations of potassium channels Kcna1 and Kcnq2 increase neuronal activity and lead to seizure disorders. We tested the hypothesis that reducing the expression of Scn8a would compensate for loss-of-function mutations of Kcna1 or Kcnq2. Scn8a expression was reduced by the administration of an antisense oligonucleotide (ASO). This treatment lengthened the survival of the Kcn1a and Kcnq2 mutants, and reduced the seizure frequency in the Kcnq2 mutant mice. These observations suggest that reduction of SCN8A may be therapeutic for genetic epilepsies resulting from mutations in these potassium channel genes.
Topics: Animals; Epilepsy; KCNQ2 Potassium Channel; Kv1.1 Potassium Channel; Mice; Mutation; NAV1.6 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Oligonucleotides, Antisense
PubMed: 35892317
DOI: 10.1111/epi.17374 -
Biomedicine & Pharmacotherapy =... Jun 2023Potassium channels play an important role in human physiological function. Recently, various molecular mechanisms have implicated abnormal functioning of potassium... (Review)
Review
Potassium channels play an important role in human physiological function. Recently, various molecular mechanisms have implicated abnormal functioning of potassium channels in the proliferation, migration, invasion, apoptosis, and cancer stem cell phenotype formation. Potassium channels also mediate the association of tumor cells with the tumor microenvironment. Meanwhile, potassium channels are important targets for cancer chemotherapy. A variety of drugs exert anti-cancer effects by modulating potassium channels in tumor cells. Therefore, there is a need to understand how potassium channels participate in tumor development and progression, which could reveal new, novel targets for cancer diagnosis and treatment. This review summarizes the roles of voltage-gated potassium channels, calcium-activated potassium channels, inwardly rectifying potassium channels, and two-pore domain potassium channels in tumorigenesis and the underlying mechanism of potassium channel-targeted drugs. Therefore, the study lays the foundation for rational and effective drug design and individualized clinical therapeutics.
Topics: Humans; Potassium Channels; Potassium Channels, Voltage-Gated; Potassium Channels, Calcium-Activated; Cell Transformation, Neoplastic; Neoplasms; Tumor Microenvironment
PubMed: 37031494
DOI: 10.1016/j.biopha.2023.114673 -
Platelets Oct 2021Potassium ions have widespread roles in cellular homeostasis and activation as a consequence of their large outward concentration gradient across the surface membrane... (Review)
Review
Potassium ions have widespread roles in cellular homeostasis and activation as a consequence of their large outward concentration gradient across the surface membrane and ability to rapidly move through K-selective ion channels. In platelets, the predominant K channels include the voltage-gated K channel Kv1.3, and the intermediate conductance Ca-activated K channel KCa3.1, also known as the Gardos channel. Inwardly rectifying potassium GIRK channels and KCa1.1 large conductance Ca-activated K channels have also been reported in the platelet, although they remain to be demonstrated using electrophysiological techniques. Whole-cell patch clamp and fluorescent indicator measurements in the platelet or their precursor cell reveal that Kv1.3 sets the resting membrane potential and KCa3.1 can further hyperpolarize the cell during activation, thereby controlling Ca influx. Kv1.3 mice exhibit an increased platelet count, which may result from an increased splenic megakaryocyte development and longer platelet lifespan. This review discusses the evidence in the literature that Kv1.3, KCa3.1. GIRK and KCa1.1 channels contribute to a number of platelet functional responses, particularly collagen-evoked adhesion, procoagulant activity and GPCR function. Putative roles for other K channels and known accessory proteins which to date have only been detected in transcriptomic or proteomic studies, are also discussed.
Topics: Animals; Blood Platelets; Humans; Mice; Potassium Channels
PubMed: 33872124
DOI: 10.1080/09537104.2021.1904135 -
Annual Review of Pharmacology and... Jan 2023Ubiquitously expressed throughout the body, ATP-sensitive potassium (K) channels couple cellular metabolism to electrical activity in multiple tissues; their unique... (Review)
Review
Ubiquitously expressed throughout the body, ATP-sensitive potassium (K) channels couple cellular metabolism to electrical activity in multiple tissues; their unique assembly as four Kir6 pore-forming subunits and four sulfonylurea receptor (SUR) subunits has resulted in a large armory of selective channel opener and inhibitor drugs. The spectrum of monogenic pathologies that result from gain- or loss-of-function mutations in these channels, and the potential for therapeutic correction of these pathologies, is now clear. However, while available drugs can be effective treatments for specific pathologies, cross-reactivity with the other Kir6 or SUR subfamily members can result in drug-induced versions of each pathology and may limit therapeutic usefulness. This review discusses the background to K channel physiology, pathology, and pharmacology and considers the potential for more specific or effective therapeutic agents.
Topics: Humans; Potassium Channels, Inwardly Rectifying; Sulfonylurea Receptors; Mutation; Adenosine Triphosphate
PubMed: 36170658
DOI: 10.1146/annurev-pharmtox-051921-123023