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BioAssay record AID 623912 submitted by Johns Hopkins Ion Channel Center: SAR Analysis for the identification of inhibitors of the two-pore domain potassium channel KCNK9 - Selectivity assay against KCNK3: FluxOR Assay CRC 2.
BioAssay record AID 588761 submitted by Johns Hopkins Ion Channel Center: SAR Analysis for the identification of selective inhibitors of the two-pore domain potassium channel KCNK9 in KCNQ2 expressing cells: FluxOR Assay CRC.
Cerebellar granule neurons (CGNs) are one of the most populous cells in the mammalian brain. They express an outwardly rectifying potassium current, termed a
Research shows that rats and humans on a high-fat diet (HFD) are less sensitive to satiety signals known to act via vagal afferent pathways. We hypothesize that HFD causes an upregulation of 2-pore domain potassium channels, resulting in hyperpolarization of nodose ganglia (NG) and decreased vagal response to satiety signals, which contribute to hyperphagia. We show that a 2-week HFD caused an upregulation of 2-pore domain TWIK-related spinal cord K+ (TRESK) and TWIK-related acid-sensitive K+ 1 (TASK1) channels by 330% ± 50% and 60% ± 20%, respectively, in NG. Patch-clamp studies of isolated NG neurons demonstrated a decrease in excitability. In vivo single-unit NG recordings showed that a 2-week HFD led to a 55% reduction in firing frequency in response to CCK-8 or leptin stimulation. NG electroporation with TRESK siRNA restored NG responsiveness to CCK-8 and leptin. Rats fed a 2-week HFD consumed ~40% more calories compared with controls. Silencing NG TRESK but not TASK1 channel expression ...
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Introduction CD4+ T cells express K2P5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cell effector functions. Recently, it was shown that K2P5.1 is upregulated upon (autoimmune) T cell stimulation. The aim of this study was to correlate expression levels of K2P5.1 on T cells from patients with rheumatoid arthritis (RA) to disease activity in these patients. Methods Expression levels of K2P5.1 were measured by RT-PCR in the peripheral blood of 58 patients with RA and correlated with disease activity parameters (C-reactive protein levels, erythrocyte sedimentation rates, disease activity score (DAS28) scores). Twenty patients undergoing therapy change were followed-up for six months. Additionally, synovial fluid and synovial biopsies were investigated for T lymphocytes expressing K2P5.1. Results K2P5.1 expression levels in CD4+ T cells show a strong correlation to DAS28 scores in RA ...
Previously published results from our laboratory identified a mechano-gated two-pore domain potassium channel, TREK-1, as a main mechanosensor in the smooth muscle of the human urinary bladder. One of the limitations of in vitro experiments on isolated human detrusor included inability to evaluate in vivo effects of TREK-1 on voiding function, as the channel is also expressed in the nervous system, and may modulate micturition via neural pathways. Therefore, in the present study, we aimed to assess the role of TREK-1 channel in bladder function and voiding patterns in vivo by using TREK-1 knockout (KO) mice. Adult C57BL/6 J wild-type (WT, N = 32) and TREK-1 KO (N = 33) mice were used in this study. The overall phenotype and bladder function were evaluated by gene and protein expression of TREK-1 channel, in vitro contractile experiments using detrusor strips in response to stretch and pharmacological stimuli, and cystometry in unanesthetized animals. TREK-1 KO animals had an elevated basal muscle tone
Polyunsaturated fatty acid (PUFA)-activated two-pore domain potassium channels (K2P ) have been proposed to be expressed in the pulmonary vasculature. However, their physiological or pathophysiological roles are poorly defined. Here, we tested the hypothesis that PUFA-activated K2P are involved in pulmonary vasorelaxation and that alterations of channel expression are pathophysiologically linked to pulmonary hypertension. Expression of PUFA-activated K2P in the murine lung was investigated by quantitative reverse-transcription polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), by patch clamp (PC) and myography. K2P -gene expression was examined in chronic hypoxic mice. qRT-PCR showed that the K2P 2.1 and K2P 6.1 were the predominantly expressed K2P in the murine lung. IHC revealed protein expression of K2P 2.1 and K2P 6.1 in the endothelium of pulmonary arteries and of K2P 6.1 in bronchial epithelium. PC showed pimozide-sensitive K2P -like K(+) -current activated by docosahexaenoic ...
Myometrial relaxation of mouse via expression of two-pore domain acid sensitive (TASK) channels was studied. In our previous report, we suggested that two-pore domain acid-sensing K(+) channels (TASK-2) might be one of the candidates for the regulation of uterine circular smooth muscles in mice. In this study, we tried to show the mechanisms of relaxation via TASK-2 channels in marine myometrium. Isometric contraction measurements and patch clamp technique were used to verify TASK conductance in murine myometrium. Western blot and immunehistochemical study under confocal microscopy were used to investigate molecular identity of TASK channel. In this study, we showed that TEA and 4-AP insensitive non-inactivating outward K(+) current (NIOK) may be responsible for the quiescence of murine pregnant longitudinal myometrium. The characteristics of NIOK coincided with two-pore domain acid-sensing K(+) channels (TASK-2). NIOK in the presence of K(+) channel blockers was inhibited further by TASK inhibitors
Objective:To investigate the expression of two-pore domain potassium channel-TREK-1 on primary cultured neurons and astrocytes and the temporal changes of TREK-1 expression in astrocytes under hypoxia insult.Methods: The cortical neurons and astrocytes were cultured.The expression of TREK-1 in cultured neurons and astrocytes were analyzed by double immunofluorescence staining.The temporal changes of TREK-1 expression in astrocytes under hypoxia insults were detected by Real-time PCR.Results: The TREK-1 immuno-reactivity was expressed on both the neurons and astrocytes under normal condition.During hypoxia insult,the TREK-1 expression on astrocyte increases at early phases and decreases gradually at late phase.Conclusion: The TREK-1 immunoreactivity is expressed on both the neurons and astrocytes.In astrocytes under hypoxia,there are temporal changes on TREK-1 expression.
Background Brain ischemia is known to include neuronal cell death and persisting neurological deficits. A lack of oxygen and glucose are considered to be key mediators of ischemic neurodegeneration while the exact mechanisms are yet unclear. In former studies the expression of two different two-pore domain potassium \((K_{2P})\) channels (TASK1, TREK1) were shown to ameliorate neuronal damage due to cerebral ischemia. In neurons, TASK channels carrying hyperpolarizing \(K^+\) leak currents, and the pacemaker channel HCN2, carrying depolarizing \(I_h\), stabilize the membrane potential by a mutual functional interaction. It is assumed that this ionic interplay between TASK and HCN2 channels enhances the resistance of neurons to insults accompanied by extracellular pH shifts. Methods In C57Bl/6 (wildtype, WT), \(hcn2^{+/+}\) and \(hcn2^{-/-}\) mice we used an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of HCN2 in stroke ...
Potassium channels, found throughout the animal and plant kingdoms, play important roles in maintaining membrane potentials and regulating action potential firing, shape, and duration, among other functions. Using the Xenopus laevis (frog) oocyte as model system, we induced high expression of sodium and potassium voltage-gated channels and recorded action potentials by a modification of the two-electrode voltage-clamp recording technique. The voltage-dependent sodium conductance was due to expression of the skeletal muscle NaV channel (NaV1.4) and the delayed rectifier voltage-dependent potassium conductance was due to expression of a Shaker (Kv1) potassium channel. Upon this background, we mixed different potassium-selective ion channels, such as inwardly rectifying potassium (KIR) channels, tandem pore domain (K2P) potassium channels and voltage-gated (KV) channels. We analyzed how these potassium channels affected firing thresholds, reliability of action potential generation, action potential
in the normal resting state, the nerve has a negative membrane potential of -70 mv. this resting potential is determined by the concentration gradients of 2 major ions, na+ and k+, and the relative membrane permeability to these ions (also known as leak currents). the concentration gradients are maintained by the sodium/potassium atp pump (in an energy-dependent process) that transports sodium ions out of the cell and potassium ions into the cell. this active transport creates a concentration gradient that favors the extracellular diffusion of potassium ions. in addition, because the nerve membrane is permeable to potassium ions and impermeable to sodium ions, 95% of the ionic leak in excitable cells is caused by k+ ions in the form of an outward flux, accounting for the negative resting potential. the recently identified 2-pore domain potassium (k2p) channels are believed to be responsible for leak k+ currents ...
Outward rectifying potassium channel. Produces rapidly activating outward rectifier K(+) currents. May function as background potassium channel that sets the resting membrane potential. Channel activity is directly activated by calcium signal. Activated by the G(q)-protein coupled receptor pathway. The calcium signal robustly activates the channel via calcineurin, whereas the anchoring of 14-3-3/YWHAH interferes with the return of the current to the resting state after activation. Inhibited also by arachidonic acid and other naturally occurring unsaturated free fatty acids. Channel activity is also enhanced by volatile anesthetics, such as isoflurane. Appears to be the primary target of hydroxy-alpha-sanshool, an ingredient of Schezuan pepper. May be involved in the somatosensory function with special respect to pain sensation (By similarity).
Outward rectifying potassium channel. Produces rapidly activating outward rectifier K(+) currents. May function as background potassium channel that sets the resting membrane potential. Channel activity is directly activated by calcium signal. Activated by the G(q)-protein coupled receptor pathway. The calcium signal robustly activates the channel via calcineurin, whereas the anchoring of 14-3-3/YWHAH interferes with the return of the current to the resting state after activation. Inhibited also by arachidonic acid and other naturally occurring unsaturated free fatty acids. Channel activity is also enhanced by volatile anesthetics, such as isoflurane. Appears to be the primary target of hydroxy-alpha-sanshool, an ingredient of Schezuan pepper. May be involved in the somatosensory function with special respect to pain sensation.
Several recent ion channel structures have revealed large side portals, or fenestrations at the interface between their transmembrane helices that potentially expose the ion conduction pathway to the lipid core of the bilayer. In a recent study we demonstrated that functional activity of the TWIK-1 K2P channel is influenced by the presence of hydrophobic residues deep within the inner pore. These residues are located near the fenestrations in the TWIK-1 structure and promote dewetting of the pore by forming a hydrophobic barrier to ion conduction. During our previous MD simulations, lipid tails were observed to enter these fenestrations. In this addendum to that study, we investigate lipid contribution to the dewetting process. Our results demonstrate that lipid tails from both the upper and lower leaflets can occupy the fenestrations and partially penetrate into the pore. The lipid tails do not sterically occlude the pore, but there is an inverse correlation between the presence of water within the
Two-pore domain K(+) (K2P) channels play an important role tuning β-cell glucose-stimulated insulin secretion (GSIS). The K2P channel TALK-1 is linked to type-2 diabetes risk through a coding sequence polymorphism (rs1535500); however, its physiological function has remained elusive. Here, we show that TALK-1 channels are expressed in mouse and human β-cells, where they serve as key regulators of electrical excitability and GSIS. We find that the rs1535500 polymorphism, which results in an alanine to glutamate substitution in the C-terminus (Ct) of human TALK-1, increases channel activity. Genetic ablation of TALK-1 results in β-cell membrane potential (Vm) depolarization, increased islet Ca(2+) influx, and enhanced 2(nd) phase GSIS. Moreover, mice lacking TALK-1 channels are resistant to high-fat diet induced elevations in fasting glycemia. These findings reveal TALK-1 channels as important modulators of 2(nd) phase insulin secretion, and suggest a clinically relevant mechanism for ...
en] The acid-sensitive, two-pore domain K(+) channel, TASK-1, contributes to the background K(+) conductance and membrane potential (Em) of rat and human pulmonary artery (PA) smooth muscle cells (SMC), but its role in regulating tone remains elusive. This study aimed to clarify the role of TASK-1 by determining the functional properties of PA from mice in which the TASK-1 gene was deleted (TASK-1/3 KO), in comparison with wild type (WT) C57BL/6 controls. Small vessel wire myography was used to measure isometric tension developed by intact PA. Em and currents were recorded from freshly isolated PASMC using the perforated patch-clamp technique. Reverse-transcription polymerase chain reaction (RT-PCR) was used to estimate K(+) channel expression. We could find no difference between PA from WT and TASK-1/3 KO TASK KO mice. They showed similar constrictor responses to a range of agonists and K(+) concentrations, the K(+) channel blockers 4-aminopyridine, tetraethylammonuim ions and XE991. ...
A combined systematic alanine scanning and molecular modelling approach reveals the molecular basis for an allosteric inhibition mechanism of K+-flux gating in K2P channels.
Author(s): Zilberberg, N; Ilan, N; Goldstein, SA | Abstract: Essential to nerve and muscle function, little is known about how potassium leak channels operate. KCNKØ opens and closes in a kinase-dependent fashion. Here, the transition is shown to correspond to changes in the outer aspect of the ion conduction pore. Voltage-gated potassium (VGK) channels open and close via an internal gate; however, they also have an outer pore gate that produces C-type inactivation. While KCNKØ does not inactivate, KCNKØ and VGK channels respond in like manner to outer pore blockers, potassium, mutations, and chemical modifiers. Structural relatedness is confirmed: VGK residues that come close during C-type gating predict KCNKØ sites that crosslink (after mutation to cysteine) to yield channels controlled by reduction and oxidization. We conclude that similar outer pore gates mediate KCNKØ opening and closing and VGK channel C-type inactivation despite their divergent structures and physiological roles.
TASK-2 (KCNK5) two-pore domain, pH-sensitive, voltage-insensitive, outward rectifying K+ channel (K+ , Rb+ ,, Cs+ , NH4+ , Na+ ≈ Li+), present in renal epithelia. Regulated [inhibited] via group 1 metabolotropic glutamate receptors and by inositol phosphates (Chemin et al., 2003). TASK-2 gating is controlled by changes in both extra- and intracellular pH through separate sensors: arginine 224 and lysine 245, located at the extra- and intracellular ends of transmembrane domain 4, respectively. TASK-2 is inhibited by a direct effect of CO2 and is regulated by and interacts with G protein subunits. TASK-2 takes part in regulatory adjustments and is a mediator in the chemoreception process in neurons of the retrotrapezoid nucleus where its pHi sensitivity could be important in regulating excitability and therefore signalling of the O2/CO2 status. Extracellular pH increases, brought about by HCO3- efflux from proximal tubule epithelial cells may couple to TASK-2 activation to maintain ...
Complete information for KCNK6 gene (Protein Coding), Potassium Two Pore Domain Channel Subfamily K Member 6, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
Trek grading and walking times are average estimates only for people of average fitness and who are well acclimatised to the altitude. Some people will be much faster and others will find it more difficult and be much slower. Estimated times have been based on our experience with previous groups. Your own hiking speeds will depend on how well you have adjusted to the altitude as well as your own personal fitness level. The effects of altitude do make the hiking much harder than a similar trek closer to sea level would be and different people adjust to the altitude in a different timeframe.. You need to have average to good fitness and be able to hike a sustained uphill climb for up to 3 hours without distress and manage the long descents down from the passes to be able to enjoy these treks, and also be able to manage several nights sleeping in tents in sometimes very cold conditions.. We have graded most of the Huayhuash treks to be Hard. This not because of the technical difficulty of the treks ...
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The Trek Remedy was a great model for the Wisconsin brand. The bike was a great looking 6in all-mountain bike. Triple chainring, ride up hill, bomb down the other, kind of machine. At Singletrack, we loved it (save for some the slightly cheaper feeling bars) - well, now for 2010, Trek has sprinkled Carbon Pixie Dust over the Remedy, given it 150/150 travel and, as with all recent Treks, made it look really great.. Lets start with the aluminium model. A completely new frame, 150mm Fox TALAS fork, good looking graphics, an E2 tapered steerer/headtube and, what else? The two aluminium models gain ISCG mounts and all new Remedys will have a magnesium rocker. The bikes we saw are still protos, but they reckon the ally bike will come in around 29lb, if not less.. ...
Saw it today. This was not Star Trek. These could have been any characters, in any science fiction setting. There was nothing Star Trek about this...
This challenging trek combines the stunning Salkantay trek with the world famous Inca Trail Trek. Walk in the shadow of Salkantay,
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KATP channels k amagra act as an electrical transducer of the metabolic state of the cell and are inhibited when cellular phosphorylation potential is high, whereas they are activated and open kamagra gratis verzending metabolism decreases. 72. 45. Neuro-Ophthalmology 1985;521в25.
Complete information for KCNK10 gene (Protein Coding), Potassium Two Pore Domain Channel Subfamily K Member 10, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
Either it is a happy coincidence that my daughter suddenly likes to be worn, or the Chimparoo Trek is the magical soft-structured carrier Ive been waiting for. In the four months of her existence, weve explored just about every category of babywearing (structured, semi-structured/soft, wraps and slings). She will not tolerate any of them! I cant say I blame her … I feel extremely claustrophobic and uncomfortable in wraps and slings.. Before getting the Chimparoo Trek, I was pretty convinced it would be another failed attempt at babywearing and I would just have to give up on the idea. I am happy to say that I was wrong! The first time we tried it, Ava (at 3 months) lasted about five minutes. The next day we reached 10 minutes and since then shes happy in it for over an hour!. So far I have only worn her in the front carry position because of her size. She sits snugly in the built-in stretchy fabric infant seat. There is also a head support (made from the same stretchy fabric) that is ...
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Druk Path Trek is a short & moderate grade trek executed between the two beautiful valleys, viz. Paro and Thimpu that necessitates you to cross the chain of mountains separating them. You can relish the view of alpine lakes and fascinating Himalayas.......
Regular readers know that Ive been a big Star Trek geek (more or less) ever since I first discovered reruns of the original Star Trek episodes in the 1970s, having been too young (but not by much!) to have caught the show during its original 1966-1969 run.
Formally one of many underused aliens with ties to the Federation, the Efrosians have now become reasonably prominant in Trek lit, ever since Star...
Annapurna Circuit Trek lets you immerse within in the Himalayan lifestyle with panoramic views of mountain ranges, captivating sunrises and terraced farmlands.
Annapurna Circuit trek is a classic trekking around the worlds tenth highest mountain. Annapurna Circuit trekking can depart any date for group of two persons and more.
Recombinant protein of human potassium channel, subfamily K, member 6 (KCNK6), 20 ug available for purchase from OriGene - Your Gene Company.
This is a lot of 7 Star Trek paperbacks: #31 Battlestations!, #32 Chain of Attack, #33 Deep Domain, #34 Dreams of the Raven, #35 The Romulan Way, #36
The first class cabin of Qantas's A380 super-jumbos looks astonishingly like the U.S.S. Enterprise in Star Trek - although you'll have to settle for earthly routes such as London to Sydney.
In the opening scene of Star Trek Into Darkness, Spock almost gets baked alive as he ventures into the maw of a volcano thats about to erupt on plane
If, like most right-thinking people, you were slightly disappointed by the latest Star Trek movie, then be prepared to be disappointed by it all over again - albeit in far more (and probably far geeki...
This week, it feels like Star Trek is everywhere. Ive read more about old characters and new characters and new actors playing old characters, whether the new movie counts as even-numbered or odd-numbered, and various other lists and updates and theorie
This bike started life as a Trek Fuel EX 8, but all that remains of the original bike is the frame, the seatpost, the front fork and the brakes.
Based on my rambling, she was confident she had found the bike for me. By this point, I knew what didnt work but I wasnt 100% certain what would work for me and I was ready to take a leap of faith after she read me the dimensions. Peggy said she talked to Trek and they had one bike in this size in a warehouse somewhere in California ...
VideoThe first teaser trailer for director J.J. Abrams upcoming sci-fi sequel blockbuster Star Trek Into Darkness has hit the Web, dear readers. After months of speculation and fans wondering just what is in store for the crew of the Enterprise, we finally get some answers. But if youre looking for confirmation [...]
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