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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 -
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 -
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 -
Cellular and Molecular Life Sciences :... Oct 2015Potassium channels ubiquitously exist in nearly all kingdoms of life and perform diverse but important functions. Since the first atomic structure of a prokaryotic... (Review)
Review
Potassium channels ubiquitously exist in nearly all kingdoms of life and perform diverse but important functions. Since the first atomic structure of a prokaryotic potassium channel (KcsA, a channel from Streptomyces lividans) was determined, tremendous progress has been made in understanding the mechanism of potassium channels and channels conducting other ions. In this review, we discuss the structure of various kinds of potassium channels, including the potassium channel with the pore-forming domain only (KcsA), voltage-gated, inwardly rectifying, tandem pore domain, and ligand-gated ones. The general properties shared by all potassium channels are introduced first, followed by specific features in each class. Our purpose is to help readers to grasp the basic concepts, to be familiar with the property of the different domains, and to understand the structure and function of the potassium channels better.
Topics: Dimerization; Ion Channel Gating; Models, Molecular; Potassium Channels; Protein Structure, Tertiary; Species Specificity
PubMed: 26070303
DOI: 10.1007/s00018-015-1948-5 -
IUBMB Life Feb 2009Mitochondrial potassium channels are believed to contribute to cytoprotection of injured cardiac and neuronal tissues. The following potassium channels have been... (Review)
Review
Mitochondrial potassium channels are believed to contribute to cytoprotection of injured cardiac and neuronal tissues. The following potassium channels have been described in the inner mitochondrial membrane: the ATP-regulated potassium channel, the large conductance Ca(2+)-activated potassium channel, the voltage-gated Kv1.3 potassium channel, and the twin-pore domain TASK-3 potassium channel. The putative functional roles of these channels include changes in mitochondrial matrix volume, mitochondrial respiration, and membrane potential. In addition, the activity of these channels modulates the generation of reactive oxygen species by mitochondria. In this article, we discuss recent observations on three fundamental issues concerning mitochondrial potassium channels: (i) their molecular identity, (ii) their interaction with potassium channel openers and inhibitors, and (iii) their functional properties.
Topics: Adenosine Triphosphate; Animals; Calcium; Humans; Ion Channel Gating; Membrane Potentials; Mitochondria; Permeability; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Calcium-Activated; Potassium Channels, Voltage-Gated; Reactive Oxygen Species
PubMed: 19165895
DOI: 10.1002/iub.155 -
Neuron Nov 2001What is the moving part that switches an ion channel's current on and off? In this issue of Neuron del Camino and Yellen (2001) exploit scanning cysteine mutagenesis and... (Review)
Review
What is the moving part that switches an ion channel's current on and off? In this issue of Neuron del Camino and Yellen (2001) exploit scanning cysteine mutagenesis and sulfhydryl reagents to show that the intracellular end of the S6 helices forms a mechanical gate for the Shaker potassium channel.
Topics: Animals; Ion Channel Gating; Mutagenesis; Neurons; Potassium Channels
PubMed: 11719196
DOI: 10.1016/s0896-6273(01)00509-8 -
The Journal of Biological Chemistry Nov 2018Potassium channels that exhibit the property of inward rectification (Kir channels) are present in most cells. Cloning of the first Kir channel genes 25 years ago led to... (Review)
Review
Potassium channels that exhibit the property of inward rectification (Kir channels) are present in most cells. Cloning of the first Kir channel genes 25 years ago led to recognition that inward rectification is a consequence of voltage-dependent block by cytoplasmic polyamines, which are also ubiquitously present in animal cells. Upon cellular depolarization, these polycationic metabolites enter the Kir channel pore from the intracellular side, blocking the movement of K ions through the channel. As a consequence, high K conductance at rest can provide very stable negative resting potentials, but polyamine-mediated blockade at depolarized potentials ensures, for instance, the long plateau phase of the cardiac action potential, an essential feature for a stable cardiac rhythm. Despite much investigation of the polyamine block, where exactly polyamines get to within the Kir channel pore and how the steep voltage dependence arises remain unclear. This Minireview will summarize current understanding of the relevance and molecular mechanisms of polyamine block and offer some ideas to try to help resolve the fundamental issue of the voltage dependence of polyamine block.
Topics: Ion Transport; Polyamines; Potassium; Potassium Channels; Protein Conformation
PubMed: 30333230
DOI: 10.1074/jbc.TM118.003344 -
The Journal of Cell Biology Jul 2014Potassium channels are pore-forming transmembrane proteins that regulate a multitude of biological processes by controlling potassium flow across cell membranes.... (Review)
Review
Potassium channels are pore-forming transmembrane proteins that regulate a multitude of biological processes by controlling potassium flow across cell membranes. Aberrant potassium channel functions contribute to diseases such as epilepsy, cardiac arrhythmia, and neuromuscular symptoms collectively known as channelopathies. Increasing evidence suggests that cancer constitutes another category of channelopathies associated with dysregulated channel expression. Indeed, potassium channel-modulating agents have demonstrated antitumor efficacy. Potassium channels regulate cancer cell behaviors such as proliferation and migration through both canonical ion permeation-dependent and noncanonical ion permeation-independent functions. Given their cell surface localization and well-known pharmacology, pharmacological strategies to target potassium channel could prove to be promising cancer therapeutics.
Topics: Cell Cycle; Cell Movement; Cell Proliferation; Humans; Models, Biological; Neoplasm Metastasis; Neoplasms; Potassium Channel Blockers; Potassium Channels; Tumor Microenvironment
PubMed: 25049269
DOI: 10.1083/jcb.201404136 -
The Journal of Physiology Jun 2015The most essential properties of ion channels for their physiologically relevant functions are ion-selective permeation and gating. Among the channel species, the... (Review)
Review
The most essential properties of ion channels for their physiologically relevant functions are ion-selective permeation and gating. Among the channel species, the potassium channel is primordial and the most ubiquitous in the biological world, and knowledge of this channel underlies the understanding of features of other ion channels. The strategy applied to studying channels changed dramatically after the crystal structure of the potassium channel was resolved. Given the abundant structural information available, we exploited the bacterial KcsA potassium channel as a simple model channel. In the postcrystal age, there are two effective frameworks with which to decipher the functional codes present in the channel structure, namely reconstitution and re-animation. Complex channel proteins are decomposed into essential functional components, and well-examined parts are rebuilt for integrating channel function in the membrane (reconstitution). Permeation and gating are dynamic operations, and one imagines the active channel by breathing life into the 'frozen' crystal (re-animation). Capturing the motion of channels at the single-molecule level is necessary to characterize the behaviour of functioning channels. Advanced techniques, including diffracted X-ray tracking, lipid bilayer methods and high-speed atomic force microscopy, have been used. Here, I present dynamic pictures of the KcsA potassium channel from the submolecular conformational changes to the supramolecular collective behaviour of channels in the membrane. These results form an integrated picture of the active channel and offer insights into the processes underlying the physiological function of the channel in the cell membrane.
Topics: Cell Membrane; Humans; Ion Channel Gating; Potassium Channels
PubMed: 25833254
DOI: 10.1113/JP270025 -
Molecules (Basel, Switzerland) Jan 2022Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and... (Review)
Review
Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and synthesis of reactive oxygen species (ROS). It has been found that pharmacological activation of mitochondrial potassium channels during ischemia/reperfusion (I/R) injury activates cytoprotective mechanisms resulting in increased cell survival. In cancer cells, the inhibition of these channels leads to increased cell death. Therefore, mitochondrial potassium channels are intriguing targets for the development of new pharmacological strategies. In most cases, however, the substances that modulate the mitochondrial potassium channels have a few alternative targets in the cell. This may result in unexpected or unwanted effects induced by these compounds. In our review, we briefly present the various classes of mitochondrial potassium (mitoK) channels and describe the chemical compounds that modulate their activity. We also describe examples of the multidirectional activity of the activators and inhibitors of mitochondrial potassium channels.
Topics: Adenosine Triphosphate; Animals; Calcium; Humans; Ion Channel Gating; Mitochondrial Membrane Transport Proteins; Potassium; Potassium Channel Blockers; Potassium Channels
PubMed: 35011530
DOI: 10.3390/molecules27010299