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Hisao Tsukamoto, Masahiro Higashi, Hideyoshi Motoki, Hiroki Watanabe, Christian Ganser, Koichi Nakajo, Yoshihiro Kubo, Takayuki Uchihashi, Yuji Furutani
Canonical K+ channels are tetrameric and highly K+ selective, whereas two-pore domain K+ (K2P) channels form dimers, but with a similar pore architecture. A two-pore domain potassium channel TWIK1 (KCNK1 or K2P1) allows permeation of Na+ and other monovalent ions, resulting mainly from the presence of Thr118 in the P1 domain. However, the mechanistic basis for this reduced selectivity is unclear. Using ion-exchange-induced difference infrared spectroscopy, we analyzed WT TWIK1 and T118I (highly K+ selective) and L228F (substitution in the P2 domain) TWIK1 variants and found that in the presence of K+ ions, WT and both variants exhibit an amide-I band at 1680 cm-1 This band corresponds to interactions of the backbone carbonyls in the selectivity filter with K+ , a feature very similar to that of the canonical K+ channel KcsA...
March 15, 2018: Journal of Biological Chemistry
Yotesawee Srisomboon, Nathan A Zaidman, Peter J Maniak, Chatsri Deachapunya, Scott M O'Grady
The objective of this study was to determine the molecular identity of ion channels involved in K+ secretion by the mammary epithelium and to examine their regulation by purinoceptor agonists. Apical membrane voltage clamp experiments were performed on human mammary epithelial cells where the basolateral membrane was exposed to the pore-forming antibiotic amphotericin B dissolved in a solution with intracellular-like ionic composition. Addition of the Na+ channel inhibitor benzamil reduced the basal current, consistent with inhibition of Na+ uptake across the apical membrane whereas the KCa 3...
January 24, 2018: American Journal of Physiology. Cell Physiology
Paul D Wright, Emma L Veale, David McCoull, David C Tickle, Jonathan M Large, Emma Ococks, Gemma Gothard, Catherine Kettleborough, Alistair Mathie, Jeffrey Jerman
Two-pore domain potassium channels (K2Ps) are characterized by their four transmembrane domain and two-pore topology. They carry background (or leak) potassium current in a variety of cell types. Despite a number of important roles there is currently a lack of pharmacological tools with which to further probe K2P function. We have developed a cell-based thallium flux assay, using baculovirus delivered TASK3 (TWIK-related acid-sensitive K+ channel 3, KCNK9, K2P9.1) with the aim of identifying novel, selective TASK3 activators...
November 4, 2017: Biochemical and Biophysical Research Communications
Kanghyun Ryoo, Jae-Yong Park
Two-pore domain potassium (K2P) channels have a distinct structure and channel properties, and are involved in a background K(+) current. The 15 members of the K2P channels are identified and classified into six subfamilies on the basis of their sequence similarities. The activity of the channels is dynamically regulated by various physical, chemical, and biological effectors. The channels are expressed in a wide variety of tissues in mammals in an isoform specific manner, and play various roles in many physiological and pathophysiological conditions...
October 2016: Experimental Neurobiology
Xiang-Yao Li, Hiroki Toyoda
Potassium (K(+)) channels are membrane proteins that allow rapid and selective flow of K(+) ions across the cell membrane, generating electrical signals in neurons. Thus, K(+) channels play a critical role in determining the neuronal excitability. Two-pore domain (K2P) "leak" K(+) channels give rise to leak K(+) currents that are responsible for the resting membrane potential and input resistance. The wide expression of leak K(+) channels in the central and peripheral nervous system suggests that these channels are critically involved in pain signaling and behavior...
October 2015: Brain Research Bulletin
Sylvain Feliciangeli, Frank C Chatelain, Delphine Bichet, Florian Lesage
Potassium channels participate in many biological functions, from ion homeostasis to generation and modulation of the electrical membrane potential. They are involved in a large variety of diseases. In the human genome, 15 genes code for K(+) channels with two pore domains (K2P ). These channels form dimers of pore-forming subunits that produce background conductances finely regulated by a range of natural and chemical effectors, including signalling lipids, temperature, pressure, pH, antidepressants and volatile anaesthetics...
June 15, 2015: Journal of Physiology
Alistair Mathie, Emma L Veale
Recent evidence points to a pivotal contribution of a variety of different potassium channels, including two-pore domain potassium (K2P) channels, in chronic pain processing. Expression of several different K2P channel subunits has been detected in nociceptive dorsal root ganglion neurons and trigeminal ganglion neurons, in particular, TREK1, TREK2, TRESK, TRAAK, TASK3 and TWIK1 channels. Of these, the strongest body of evidence from functional studies highlights the importance of TREK1, TRESK and, recently, TREK2 channels...
May 2015: Pflügers Archiv: European Journal of Physiology
Delphine Bichet, Sandy Blin, Sylvain Feliciangeli, Franck C Chatelain, Nicole Bobak, Florian Lesage
Among K2P channels, a few of them turned out to be difficult to express in heterologous systems and were coined "silent subunits". Recent studies have shed light on the mechanisms behind this apparent lack of channel activity at the plasma membrane. For TWIK1 and THIK2 channels, silence is related to a combination of intracellular retention and low intrinsic activity. TWIK1 is constitutively endocytosed from the plasma membrane before being transported to recycling endosomes, whereas THIK2 is restricted to endoplasmic reticulum...
May 2015: Pflügers Archiv: European Journal of Physiology
Haijun Chen, Franck C Chatelain, Florian Lesage
K(+) channels play a key role in regulating cellular excitability. It was thought that the strong K(+) selectivity of these channels was static, only altered by mutations in their selectivity filter, which can cause severe genetic disorders. Recent studies demonstrate that selectivity of K(+) channels can also exhibit dynamic changes. Under acidic conditions or in low extracellular K(+) concentrations, the two-pore domain K(+) channel (K2P) TWIK1 becomes permeable to Na(+), shifting from an inhibitory role to an excitatory role...
September 2014: Trends in Pharmacological Sciences
Sarah L Pollema-Mays, Maria Virginia Centeno, Crystle J Ashford, A Vania Apkarian, Marco Martina
Neuropathic pain is associated with hyperexcitability of DRG neurons. Despite the importance of leakage potassium channels for neuronal excitability, little is known about their cell-specific expression in DRGs and possible modulation in neuropathic pain. Multiple leakage channels are expressed in DRG neurons, including TASK1, TASK3, TRESK, TRAAK, TWIK1, TREK1 and TREK2 but little is known about their distribution among different cell types. Our immunohistochemical studies show robust TWIK1 expression in large and medium size neurons, without overlap with TRPV1 or IB4 staining...
November 2013: Molecular and Cellular Neurosciences
Franck C Chatelain, Delphine Bichet, Dominique Douguet, Sylvain Feliciangeli, Saïd Bendahhou, Markus Reichold, Richard Warth, Jacques Barhanin, Florian Lesage
TWIK1 belongs to the family of background K(+) channels with two pore domains. In native and transfected cells, TWIK1 is detected mainly in recycling endosomes. In principal cells in the kidney, TWIK1 gene inactivation leads to the loss of a nonselective cationic conductance, an unexpected effect that was attributed to adaptive regulation of other channels. Here, we show that TWIK1 ion selectivity is modulated by extracellular pH. Although TWIK1 is K(+) selective at neutral pH, it becomes permeable to Na(+) at the acidic pH found in endosomes...
April 3, 2012: Proceedings of the National Academy of Sciences of the United States of America
Joseph Yanni, James O Tellez, Michal Maczewski, Urszula Mackiewicz, Andrzej Beresewicz, Rudi Billeter, Halina Dobrzynski, M R Boyett
BACKGROUND: Heart failure (HF) causes a decline in the function of the pacemaker of the heart-the sinoatrial node (SAN). The aim of the study was to investigate HF-induced changes in the expression of the ion channels and related proteins underlying the pacemaker activity of the SAN. METHODS AND RESULTS: HF was induced in rats by the ligation of the proximal left coronary artery. HF animals showed an increase in the left ventricular (LV) diastolic pressure (317%) and a decrease in the LV systolic pressure (19%) compared with sham-operated animals...
July 2011: Circulation. Heart Failure
Alistair Mathie, Kathryn A Rees, Mickael F El Hachmane, Emma L Veale
The activity of two pore domain potassium (K2P) channels regulates neuronal excitability and cell firing. Post-translational regulation of K2P channel trafficking to the membrane controls the number of functional channels at the neuronal membrane affecting the functional properties of neurons. In this review, we describe the general features of K channel trafficking from the endoplasmic reticulum (ER) to the plasma membrane via the Golgi apparatus then focus on established regulatory mechanisms for K2P channel trafficking...
September 2010: Current Neuropharmacology
Sylvain Feliciangeli, Magalie P Tardy, Guillaume Sandoz, Franck C Chatelain, Richard Warth, Jacques Barhanin, Saïd Bendahhou, Florian Lesage
Tandem of P domains in a weak inwardly rectifying K(+) channel 1 (TWIK1) is a K(+) channel that produces unusually low levels of current. Replacement of lysine 274 by a glutamic acid (K274E) is associated with stronger currents. This mutation would prevent conjugation of a small ubiquitin modifier peptide to Lys-274, a mechanism proposed to be responsible for channel silencing. However, we found no biochemical evidence of TWIK1 sumoylation, and we showed that the conservative change K274R did not increase current, suggesting that K274E modifies TWIK1 gating through a charge effect...
February 12, 2010: Journal of Biological Chemistry
Christina C Young, Michael Stegen, René Bernard, Martin Müller, Josef Bischofberger, Rüdiger W Veh, Carola A Haas, Jakob Wolfart
In humans, temporal lobe epilepsy (TLE) is often associated with Ammon's horn sclerosis (AHS) characterized by hippocampal cell death, gliosis and granule cell dispersion (GCD) in the dentate gyrus. Granule cells surviving TLE have been proposed to be hyperexcitable and to play an important role in seizure generation. However, it is unclear whether this applies to conditions of AHS. We studied granule cells using the intrahippocampal kainate injection mouse model of TLE, brain slice patch-clamp recordings, morphological reconstructions and immunocytochemistry...
September 1, 2009: Journal of Physiology
Susan I V Judge, Paul J Smith
BACKGROUND: Mechanisms of neuroprotection encompass energy deficits in brain arising from insufficient oxygen and glucose levels following respiratory failure; ischemia or stroke, which produce metabolic stresses that lead to unconsciousness and seizures; and the effects of general anesthetics. Foremost among those K(+) channels viewed as important for neuroprotection are ATP-sensitive (K(ATP)) channels, which belong to the family of inwardly rectifying K(+) channels (K(ir)) and contain a sulfonylurea subunit (SUR1 or SUR2) combined with either K(ir)6...
April 2009: Expert Opinion on Therapeutic Patents
Nathalie Gaborit, Thomas Wichter, Andras Varro, Viktoria Szuts, Guillaume Lamirault, Lars Eckardt, Matthias Paul, Günter Breithardt, Eric Schulze-Bahr, Denis Escande, Stanley Nattel, Sophie Demolombe
AIMS: Brugada syndrome is an inherited sudden-death arrhythmia syndrome. Na(+)-current dysfunction is central, but mutations in the SCN5A gene (encoding the cardiac Na(+)-channel Nav1.5) are present in only 20% of probands. This study addressed the possibility that Brugada patients display specific expression patterns for ion-channels regulating cardiac conduction, excitability, and repolarization. METHODS AND RESULTS: Transcriptional profiling was performed on right-ventricular endomyocardial biopsies from 10 unrelated Brugada probands, 11 non-diseased organ-donors, seven heart-transplant recipients, 10 with arrhythmogenic right-ventricular cardiomyopathy, and nine with idiopathic right-ventricular outflow-tract tachycardia...
February 2009: European Heart Journal
Sylvain Feliciangeli, Saïd Bendahhou, Guillaume Sandoz, Pierre Gounon, Markus Reichold, Richard Warth, Michel Lazdunski, Jacques Barhanin, Florian Lesage
A novel model for the regulation of cell excitability has recently been proposed. It originates from the observation that the background K(+) channel K2P1 (TWIK1) may be silenced by sumoylation in Xenopus oocytes and that inactivation of the putative sumoylation site (mutation K274E) gives rise to robust current expression in transfected COS-7 cells. Here, we show that only the mutation K274E, and not K274R, is associated with an increase of K2P1 current density, suggesting a charge effect of K274E. Furthermore, we failed to observe any band shift by western blot analysis that would confirm an eventual sumoylation of K2P1 in COS-7 cells and oocytes...
August 10, 2007: Cell
Nathalie Gaborit, Sabrina Le Bouter, Viktoria Szuts, Andras Varro, Denis Escande, Stanley Nattel, Sophie Demolombe
The various cardiac regions have specific action potential properties appropriate to their electrical specialization, resulting from a specific pattern of ion-channel functional expression. The present study addressed regionally defined differential ion-channel expression in the non-diseased human heart with a genomic approach. High-throughput real-time RT-PCR was used to quantify the expression patterns of 79 ion-channel subunit transcripts and related genes in atria, ventricular epicardium and endocardium, and Purkinje fibres isolated from 15 non-diseased human donor hearts...
July 15, 2007: Journal of Physiology
Sonia Decressac, Michel Franco, Said Bendahhou, Richard Warth, Sebastian Knauer, Jacques Barhanin, Michel Lazdunski, Florian Lesage
TWIK1 belongs to a family of K(+) channels involved in neuronal excitability and cell volume regulation. Its tissue distribution suggests a role in epithelial potassium transport. Here we show that TWIK1 is expressed in a subapical compartment in renal proximal tubules and in polarized MDCK cells. In nonpolarized cells, this compartment corresponds to pericentriolar recycling endosomes. We identified EFA6, an exchange factor for the small G protein ADP-ribosylation factor 6 (ARF6), as a protein binding to TWIK1...
December 2004: EMBO Reports
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