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Biochimica Et Biophysica Acta Aug 2016In this review, we summarize our knowledge about mitochondrial potassium channels, with a special focus on unanswered questions in this field. The following potassium... (Review)
Review
In this review, we summarize our knowledge about mitochondrial potassium channels, with a special focus on unanswered questions in this field. The following potassium channels have been well described in the inner mitochondrial membrane: ATP-regulated potassium channel, Ca(2+)-activated potassium channel, the voltage-gated Kv1.3 potassium channel, and the two-pore domain TASK-3 potassium channel. The primary functional roles of these channels include regulation of mitochondrial respiration and the alteration of membrane potential. Additionally, they modulate the mitochondrial matrix volume and the synthesis of reactive oxygen species by mitochondria. Mitochondrial potassium channels are believed to contribute to cytoprotection and cell death. In this paper, we discuss fundamental issues concerning mitochondrial potassium channels: their molecular identity, channel pharmacology and functional properties. Attention will be given to the current problems present in our understanding of the nature of mitochondrial potassium channels. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
Topics: Animals; Epithelial Cells; Gene Expression; Humans; Ion Transport; Mitochondria; Myocytes, Cardiac; Neurons; Organ Specificity; Plants; Potassium Channel Blockers; Potassium Channels, Calcium-Activated; Potassium Channels, Inwardly Rectifying; Potassium Channels, Tandem Pore Domain; Potassium Channels, Voltage-Gated; Saccharomyces cerevisiae; T-Lymphocytes; Trypanosomatina
PubMed: 26951942
DOI: 10.1016/j.bbabio.2016.03.007 -
Life Science Alliance Dec 2023Voltage-sensitive potassium channels play an important role in controlling membrane potential and ionic homeostasis in the gut and have been implicated in...
Voltage-sensitive potassium channels play an important role in controlling membrane potential and ionic homeostasis in the gut and have been implicated in gastrointestinal (GI) cancers. Through large-scale analysis of 897 patients with gastro-oesophageal adenocarcinomas (GOAs) coupled with in vitro models, we find family genes are mutated in ∼30% of patients, and play therapeutically targetable roles in GOA cancer growth. and mediate the WNT pathway and MYC to increase proliferation through resultant effects on cadherin junctions. This also highlights novel roles of in non-excitable tissues. We also discover that activity of KCNQ3 sensitises cancer cells to existing potassium channel inhibitors and that inhibition of KCNQ activity reduces proliferation of GOA cancer cells. These findings reveal a novel and exploitable role of potassium channels in the advancement of human cancer, and highlight that supplemental treatments for GOAs may exist through KCNQ inhibitors.
Topics: Humans; KCNQ Potassium Channels; KCNQ3 Potassium Channel; KCNQ2 Potassium Channel; Adenocarcinoma
PubMed: 37748809
DOI: 10.26508/lsa.202302124 -
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 -
Neuroscience and Biobehavioral Reviews Sep 2023Potassium channels (K-channels) selectively control the passive flow of potassium ions across biological membranes and thereby also regulate membrane excitability.... (Review)
Review
Potassium channels (K-channels) selectively control the passive flow of potassium ions across biological membranes and thereby also regulate membrane excitability. Genetic variants affecting many of the human K-channels are well known causes of Mendelian disorders within cardiology, neurology, and endocrinology. K-channels are also primary targets of many natural toxins from poisonous organisms and drugs used within cardiology and metabolism. As genetic tools are improving and larger clinical samples are being investigated, the spectrum of clinical phenotypes implicated in K-channels dysfunction is rapidly expanding, notably within immunology, neurosciences, and metabolism. K-channels that previously were considered to be expressed in only a few organs and to have discrete physiological functions, have recently been found in multiple tissues and with new, unexpected functions. The pleiotropic functions and patterns of expression of K-channels may provide additional therapeutic opportunities, along with new emerging challenges from off-target effects. Here we review the functions and therapeutic potential of K-channels, with an emphasis on the nervous system, roles in neuropsychiatric disorders and their involvement in other organ systems and diseases.
Topics: Humans; Potassium Channels; Brain Diseases; Potassium
PubMed: 37414376
DOI: 10.1016/j.neubiorev.2023.105301 -
Comprehensive Physiology Sep 2018ATP sensitive potassium channels (K ) are so named because they open as cellular ATP levels fall. This leads to membrane hyperpolarization and thus links cellular... (Review)
Review
ATP sensitive potassium channels (K ) are so named because they open as cellular ATP levels fall. This leads to membrane hyperpolarization and thus links cellular metabolism to membrane excitability. They also respond to MgADP and are regulated by a number of cell signaling pathways. They have a rich and diverse pharmacology with a number of agents acting as specific inhibitors and activators. K channels are formed of pore-forming subunits, Kir6.1 and Kir6.2, and a large auxiliary subunit, the sulfonylurea receptor (SUR1, SUR2A, and SUR2B). The Kir6.0 subunits are a member of the inwardly rectifying family of potassium channels and the sulfonylurea receptor is part of the ATP-binding cassette family of proteins. Four SURs and four Kir6.x form an octameric channel complex and the association of a particular SUR with a specific Kir6.x subunit constitutes the K current in a particular tissue. A combination of mutagenesis work combined with structural studies has identified how these channels work as molecular machines. They have a variety of physiological roles including controlling the release of insulin from pancreatic β cells and regulating blood vessel tone and blood pressure. Furthermore, mutations in the genes underlie human diseases such as congenital diabetes and hyperinsulinism. Additionally, opening of these channels is protective in a number of pathological conditions such as myocardial ischemia and stroke. © 2018 American Physiological Society. Compr Physiol 8:1463-1511, 2018.
Topics: Animals; Channelopathies; Humans; Ion Channel Gating; KATP Channels; Potassium Channel Blockers
PubMed: 30215858
DOI: 10.1002/cphy.c170048 -
The Journal of Biological Chemistry 2021Gain-of-function (GOF) mutations in the voltage-gated potassium channel subfamily Q member 1 (KCNQ1) can induce cardiac arrhythmia. In this study, it was tested whether...
Gain-of-function (GOF) mutations in the voltage-gated potassium channel subfamily Q member 1 (KCNQ1) can induce cardiac arrhythmia. In this study, it was tested whether any of the known human GOF disease mutations in KCNQ1 act by increasing the amount of KCNQ1 that reaches the cell surface-"supertrafficking." Seven of the 15 GOF mutants tested were seen to surface traffic more efficiently than the WT channel. Among these, we found that the levels of R231C KCNQ1 in the plasma membrane were fivefold higher than the WT channel. This was shown to arise from the combined effects of enhanced efficiency of translocon-mediated membrane integration of the S4 voltage-sensor helix and from enhanced post-translational folding/trafficking related to the energetic linkage of C231 with the V129 and F166 side chains. Whole-cell electrophysiology recordings confirmed that R231C KCNQ1 in complex with the voltage-gated potassium channel-regulatory subfamily E member 1 not only exhibited constitutive conductance but also revealed that the single-channel activity of this mutant is only 20% that of WT. The GOF phenotype associated with R231C therefore reflects the effects of supertrafficking and constitutive channel activation, which together offset reduced channel activity. These investigations show that membrane protein supertrafficking can contribute to human disease.
Topics: Animals; CHO Cells; Cell Membrane; Cricetulus; Gain of Function Mutation; HEK293 Cells; Humans; KCNQ1 Potassium Channel; Long QT Syndrome; Mutation; Patch-Clamp Techniques; Phenotype; Potassium; Potassium Channels; Potassium Channels, Voltage-Gated; Protein Binding
PubMed: 33600800
DOI: 10.1016/j.jbc.2021.100423 -
Philosophical Transactions of the Royal... Jun 2023The congenital short QT syndrome (SQTS) is a rare condition characterized by abbreviated rate-corrected QT (QTc) intervals on the electrocardiogram and by increased... (Review)
Review
The congenital short QT syndrome (SQTS) is a rare condition characterized by abbreviated rate-corrected QT (QTc) intervals on the electrocardiogram and by increased susceptibility to both atrial and ventricular arrhythmias and sudden death. Although mutations to multiple genes have been implicated in the SQTS, evidence of causality is particularly strong for the first three (SQT1-3) variants: these result from gain-of-function mutations in genes that encode K channel subunits responsible, respectively, for the I, I and I cardiac potassium currents. This article reviews evidence for the impact of SQT1-3 missense potassium channel gene mutations on the electrophysiological properties of I, I and I and of the links between these changes and arrhythmia susceptibility. Data from experimental and simulation studies and future directions for research in this field are considered. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.
Topics: Humans; Potassium Channels; Gain of Function Mutation; Arrhythmias, Cardiac; Mutation; Action Potentials
PubMed: 37122211
DOI: 10.1098/rstb.2022.0165 -
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 -
Neuropharmacology Dec 2017Arthropod venoms are a rich mixture of biologically active compounds exerting different physiological actions across diverse phyla and affecting multiple organ systems... (Review)
Review
Arthropod venoms are a rich mixture of biologically active compounds exerting different physiological actions across diverse phyla and affecting multiple organ systems including the central nervous system. Venom compounds can inhibit or activate ion channels, receptors and transporters with high specificity and affinity providing essential insights into ion channel function. In this review, we focus on arthropod toxins (scorpions, spiders, bees and centipedes) acting on neuronal potassium channels. A brief description of the K channels classification and structure is included and a compendium of neuronal K channels and the arthropod toxins that modify them have been listed. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'
Topics: Animals; Arthropods; Membrane Potentials; Neurons; Peptides; Potassium Channels
PubMed: 28941737
DOI: 10.1016/j.neuropharm.2017.09.025 -
The European Respiratory Journal Oct 2015Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder with various origins. All forms of PAH share a common pulmonary arteriopathy... (Review)
Review
Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder with various origins. All forms of PAH share a common pulmonary arteriopathy characterised by vasoconstriction, remodelling of the pre-capillary pulmonary vessel wall, and in situ thrombosis. Although the pathogenesis of PAH is recognised as a complex and multifactorial process, there is growing evidence that potassium channels dysfunction in pulmonary artery smooth muscle cells is a hallmark of PAH. Besides regulating many physiological functions, reduced potassium channels expression and/or activity have significant effects on PAH establishment and progression. This review describes the molecular mechanisms and physiological consequences of potassium channel modulation. Special emphasis is placed on KCNA5 (Kv1.5) and KCNK3 (TASK1), which are considered to play a central role in determining pulmonary vascular tone and may represent attractive therapeutic targets in the treatment of PAH.
Topics: Animals; Bone Morphogenetic Proteins; Cell Death; Cell Proliferation; Disease Progression; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Kv1.5 Potassium Channel; MicroRNAs; Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Potassium Channels; Potassium Channels, Tandem Pore Domain; Protein Processing, Post-Translational; Pulmonary Artery; Signal Transduction; Thrombosis; Vasoconstriction
PubMed: 26341985
DOI: 10.1183/13993003.00798-2015