2P Channels Research Articles

Combined SK and K2P channel block cardioverts atrial fibrillation in 82% of cases, doubling the efficacy of single channel block

Abstract Background Inhibiting the atrial-selective SK and K2P channels represents a promising strategy for cardioverting atrial fibrillation (AF), but its efficacy has not been evaluated in a large human cohort. Objectives This study employed in-silico trials in 1000 virtual patients (i.e., clinical trials conducted in a population of virtual human subjects through modelling and simulation) to estimate the efficacy and safety of three pharmacological interventions: single and combined SK and K2P channel block. Methods A large cohort of 1000 virtual patients was developed based on human data, to cover the electrophysiological, anatomical and structural variability encountered in clinical practice. The subset of virtual patients with AF maintenance underwent pharmacological cardioversion (Figure). Results Sustained AF was observed in 654 (65%) virtual patients. In this cohort, cardioversion efficacies of 33% (213 of 654), 43% (278 of 654) and 82% (534 of 654) were obtained for single SK, single K2P and combined channel block, respectively (Figure). The cardioversion efficacy was proportional to an increase in tissue refractoriness (increase of 45.2±43.0, 71.0±55.3 and 133.0±48.4 ms in the atrial refractory period) and depended on the ionic current profile. Virtual patients cardioverted by SK channel block presented lower K2P densities (0.008±0.002 vs. 0.006±0.002 S/mF; non-cardioverted vs. cardioverted virtual patients, respectively). Similarly, a lower SK density favoured the success of K2P channel inhibition (1.87±0.24 vs. 1.46±0.5 S/mF; non-cardioverted vs. cardioverted virtual patients, respectively). Both ionic currents had a crucial role on atrial repolarization, and thus, a synergism resulted from the polypharmacological strategy (i.e., higher efficacy than the additive effects of single channel block). All three interventions, including the multi-channel block, preserved the atrial electrophysiological function (i.e., conduction velocity and calcium transient dynamics) and thus, the atrial contractile properties (safety). Conclusion In-silico trials identify the polypharmacological SK+K2P channel block as an effective and safe strategy for AF management.

A Study of excitation functions in the interaction of α + 59Co system at 4~9MeV/Nucleon

In this work, α-induced 59Co reactions in the energy range from 11- 41MeV were used in order to study the role of pre-equilibrium emission. The experimentally measured excitation functions for residues populated via (α, n),(α, 2n),(α,3n),(α,2p),(α, 3n 2p) and (α, 4n 2p) channels in the interaction of + 59Co system available in the literature [13] were compared with theoretical predictions obtained using the statistical model code COMPLET. It was observed that at higher energy points the pure compound nucleus predictions, in general, failed to reproduce the measured data at projectile energies ~11-41MeV, this shows significant contributions from pre-equilibrium emission. The study signified both equilibrium and pre-equilibrium emissions were required to reproduce the presently measured excitation functions. An attempt was made to deduce the contribution coming from pre-equilibrium emission. It was found that the pre-equilibrium contribution increases with increasing projectile energy. Furthermore, the present result revealed a strong correlation between pre-equilibrium contribution and particle multiplicity.

Multireference calculations on the ground and lowest excited states and dissociation energy of LuF.

High level multireference calculations were performed for LuF for a total of 132 states, including four dissociation channels Lu(2D) + F(2P), Lu(2P) + F(2P), and two Lu(4F) + F(2P). The 6s, 5d, and 6p orbitals of lutetium, along with the valence 2p and 3p orbitals of fluorine, were included in the active space, allowing for the accurate description of static and dynamic correlation. The Lu(4F) + F(2P) channel has intersystem spin crossings with the Lu(2P) + F(2P) and Lu(2D) + F(2P) channels, which are discussed herein. To obtain spectroscopic constants, bond lengths, and excited states, multi-reference configuration interaction (MRCI) was used at a quadruple-ζ basis set level, correlating also the 4f electrons and corresponding orbitals. Core spin-orbit (C-MRCI) calculations were performed, revealing that 13Π0- is the first excited state closely followed by 13Π0+. In addition, the dissociation energy of LuF was determined at different levels of theory, with a range of basis sets. A balance between core correlation and a relativistic treatment of electrons is fundamental to obtain an accurate description of the dissociation energy. The best prediction was obtained with a combination of coupled-cluster single, double, and perturbative triple excitations /Douglas-Kroll-Hess third order Hamiltonian methods at a complete basis set level with a zero-point energy correction, which yields a dissociation value of 170.4kcal mol-1. Dissociation energies using density functional theory were calculated using a range of functionals and basis sets; M06-L and B3LYP provided the closest predictions to the best ab initio calculations.

TREK Channel Activation Suppresses Migraine Pain Phenotype

Activation and sensitization of trigeminal (TG) ganglia sensory neurons, leading to the release of pro-inflammatory peptides such as calcitonin gene-related peptide (CGRP), are likely a key component in migraine-related headache induction. Reducing TG neuron excitability represents therefore an attractive alternative strategy to relieve migraine pain. Here by using pharmacology and genetic invalidation ex vivo and in vivo, we demonstrate that activating TREK1- and TREK2- Two-Pore-Domain potassium ( K 2P ) channels inhibits TG neuronal firing sufficiently to fully reverse the migraine-like phenotype induced by NO-donors in rodents. Finally, targeting TREK is as efficient as treatment with CGRP antagonists, which represents one of the most effective migraine therapies. Altogether, our results demonstrate that inhibiting TG excitability by pharmacological activation of TREK channels should be considered as an alternative to the current migraine treatment.

Formation of hot hydrogen atoms from superexcited states of acetylene.

The cross sections for the formation of the H(2p) and H(2s) atoms, σ 2p and σ 2s , respectively, in photoexcitation of C2H2 were obtained in an absolute scale for studying formation and decay of superexcited states in the extreme ultraviolet range. Several superexcited states of C2H2 including multiply excited states were found in the curve of the σ 2p cross sections as a function of the incident photon energy. The same states seem to contribute to the variation in the σ 2s cross sections as well, which can be ascribed to the non-adiabatic transitions between the 2p and 2s channels. The Σ/Π symmetry-resolved cross sections for the H(2s) atom formation, and , were also obtained on an absolute scale. The coupling between the and 1Π u states was found to be small.

HCN and K2P Channels in Anesthetic Mechanisms Research.

The ability of a diverse group of agents to produce general anesthesia has long been an area of intense speculation and investigation. Over the past century, we have seen a paradigm shift from proposing that the anesthetized state arises from nonspecific interaction of anesthetics with the lipid membrane to the recognition that the function of distinct, and identifiable, membrane-embedded proteins is dramatically altered in the presence of intravenous and inhaled agents. Among proteinaceous targets, metabotropic and ionotropic receptors garnered much of the attention over the last 30 years, and it is only relatively recently that voltage-gated ion channels have clearly and rigorously been shown to be important molecular targets. In this review, we will consider the experimental issues relevant to two important ion channel anesthetic targets, HCN and K2P.

Joint Analysis of Radiative and Non-Radiative Electronic Relaxation Upon X-ray Irradiation of Transition Metal Aqueous Solutions.

L-edge soft X-ray spectroscopy has been proven to be a powerful tool to unravel the peculiarities of electronic structure of transition metal compounds in solution. However, the X-ray absorption spectrum is often probed in the total or partial fluorescence yield modes, what leads to inherent distortions with respect to the true transmission spectrum. In the present work, we combine photon- and electron-yield experimental techniques with multi-reference first principles calculations. Exemplified for the prototypical FeCl2 aqueous solution we demonstrate that the partial yield arising from the Fe3s → 2p relaxation is a more reliable probe of the absorption spectrum than the Fe3d → 2p one. For the bonding-relevant 3d → 2p channel we further provide the basis for the joint analysis of resonant photoelectron and inelastic X-ray scattering spectra. Establishing the common energy reference allows to assign both spectra using the complementary information provided through electron-out and photon-out events.

QUANTUM-STATE DEPENDENCE OF PRODUCT BRANCHING RATIOS IN VACUUM ULTRAVIOLET PHOTODISSOCIATION OF N2

ABSTRACT The branching ratios for the N(4S) + N(2D), N(4S) + N(2P), and N(2D) + N(2D) channels are measured for the photodissociation of N 2 ( X 1 &Sgr; g + ; v ″ = 0 , J ″ ) ?> in the vacuum ultraviolet (VUV) region of 100,808–122,159 cm−1 using the VUV–VUV pump-probe approach combined with velocity-map-imaging-photoion detection. No evidence of forming the ground-state N(4S) + N(4S) products is found. No potential barrier is observed for the N(2D) + N(2D) channel, but the N(4S) + N(2P) channel has a small potential barrier of ≈740 cm−1. The branching ratios are found to depend on the symmetry of predissociative N2 states instead of the total VUV excitation energy, indicating that N2 photodissociation is nonstatistical. When the branching ratios for N(4S) + N(2D) and N(4S) + N(2P) products are plotted as a function of the VUV excitation energy for the valence N2 1Πu and 1 &Sgr; u + ?> states, oscillations in these ratios are observed demonstrating how these channels are competing with each other. These data can be used to select both the velocity and internal states of the atomic products by picking the quantum state that is excited. High-level ab initio potential energy curves of the excited N2 states are calculated to provide insight into the mechanisms for the observed branching ratios. The calculations predict that the formation of both N(4S) + N(2D) and N(4S) + N(2P) channels involves potential energy barriers, in agreement with experimental observations. A discussion of the application of the present results to astronomy, planetary sciences, and comets is given.

Light and heavy transfer products inXe136+U238multinucleon transfer reactions

Background: Multinucleon transfer reactions (MNT) are a competitive tool to populate exotic neutron-rich nuclei in a wide region of nuclei, where other production methods have severe limitations or cannot be used at all. Purpose: Experimental information on the yields of MNT reactions in comparison with theoretical calculations are necessary to make predictions for the production of neutron-rich heavy nuclei. It is crucial to determine the fraction of MNT reaction products which are surviving neutron emission or fission at the high excitation energy after the nucleon exchange. Method: Multinucleon transfer reactions in Xe136+U238 have been measured in a high-resolution γ-ray/particle coincidence experiment. The large solid-angle magnetic spectrometer PRISMA coupled to the high-resolution Advanced Gamma Tracking Array (AGATA) has been employed. Beamlike reaction products after multinucleon transfer in the Xe region were identified and selected with the PRISMA spectrometer. Coincident particles were tagged by multichannel plate detectors placed at the grazing angle of the targetlike recoils inside the scattering chamber. Results: Mass yields have been extracted and compared with calculations based on the grazing model for MNT reactions. Kinematic coincidences between the binary reaction products, i.e., beamlike and targetlike nuclei, were exploited to obtain population yields for nuclei in the actinide region and compared to x-ray yields measured by AGATA. Conclusions: No sizable yield of actinide nuclei beyond Z=93 is found to perform nuclear structure investigations. In-beam γ-ray spectroscopy is feasible for few-neutron transfer channels in U and the −2p channel populating Th isotopes.7 MoreReceived 10 June 2015DOI:https://doi.org/10.1103/PhysRevC.92.024619©2015 American Physical Society

βIV-Spectrin regulates TREK-1 membrane targeting in the heart

Cardiac function depends on the highly regulated and co-ordinate activity of a large ensemble of potassium channels that control myocyte repolarization. While voltage-gated K(+) channels have been well characterized in the heart, much less is known about regulation and/or targeting of two-pore K(+) channel (K(2P)) family members, despite their potential importance in modulation of heart function. Here, we report a novel molecular pathway for membrane targeting of TREK-1, a mechano-sensitive K(2P) channel regulated by environmental and physical factors including membrane stretch, pH, and polyunsaturated fatty acids (e.g. arachidonic acid). We demonstrate that β(IV)-spectrin, an actin-associated protein, is co-localized with TREK-1 at the myocyte intercalated disc, associates with TREK-1 in the heart, and is required for TREK-1 membrane targeting. Mice expressing β(IV)-spectrin lacking TREK-1 binding (qv(4J)) display aberrant TREK-1 membrane localization, decreased TREK-1 activity, delayed action potential repolarization, and arrhythmia without apparent defects in localization/function of other cardiac potassium channel subunits. Finally, we report abnormal β(IV)-spectrin levels in human heart failure. These data provide new insight into membrane targeting of TREK-1 in the heart and establish a broader role for β(IV)-spectrin in organizing functional membrane domains critical for normal heart function.

Pronounced effects of interchannel coupling in high-energy photoionization

The 3d core level photoemission of metallic Ag and In was measured over a wide energy range including the 2p ionization thresholds. The intensities (photoionization cross sections) of the 3d5/2 and 3d3/2 lines were observed to modulate significantly with photon energy, both absolute and relative, and this is most pronounced in the vicinity of the 2p thresholds, i.e., at photon energies about an order of magnitude above the 3d thresholds. Calculations based on the relativistic-random-phase approximation show that this effect is due to interchannel coupling of the 3d photoionization channels with the 2p channels affecting the cross section over a wide range of energies. It is argued that this is a general phenomenon in high-energy photoionization throughout the periodic table.

The inhibitor of volume‐regulated anion channels DCPIB activates TREK potassium channels in cultured astrocytes

The ethacrynic acid derivative, 4-(2-butyl-6,7-dichlor-2-cyclopentylindan-1-on-5-yl) oxobutyric acid (DCPIB) is considered to be a specific and potent inhibitor of volume-regulated anion channels (VRACs). In the CNS, DCPIB was shown to be neuroprotective through mechanisms principally associated to its action on VRACs. We hypothesized that DCPIB could also regulate the activity of other astroglial channels involved in cell volume homeostasis. Experiments were performed in rat cortical astrocytes in primary culture and in hippocampal astrocytes in situ. The effect of DCPIB was evaluated by patch-clamp electrophysiology and immunocytochemical techniques. Results were verified by comparative analysis with recombinant channels expressed in COS-7 cells. In cultured astrocytes, DCPIB promoted the activation of a K(+) conductance mediated by two-pore-domain K(+) (K(2P) ) channels. The DCPIB effect occluded that of arachidonic acid, which activates K(2P) channels K(2P) 2.1 (TREK-1) and K(2P) 10.1 (TREK-2) in cultured astrocytes. Immunocytochemical analysis suggests that cultured astrocytes express K(2P) 2.1 and K(2P) 10.1 proteins. Moreover, DCPIB opened recombinant K(2P) 2.1 and K(2P) 10.1 expressed in heterologous system. In brain slices, DCPIB did not augment the large background K(+) conductance in hippocampal astrocytes, but caused an increment in basal K(+) current of neurons. Our results indicate that the neuroprotective effect of DCPIB could be due, at least in part, to activation of TREK channels. DCPIB could be used as template to build new pharmacological tools able to increase background K(+) conductance in astroglia and neuronal cells.

N-Glycosylation-dependent Control of Functional Expression of Background Potassium Channels K2P3.1 and K2P9.1

Two-pore domain potassium (K(2P)) channels play fundamental roles in cellular processes by enabling a constitutive leak of potassium from cells in which they are expressed, thus influencing cellular membrane potential and activity. Hence, regulation of these channels is of critical importance to cellular function. A key regulatory mechanism of K(2P) channels is the control of their cell surface expression. Membrane protein delivery to and retrieval from the cell surface is controlled by their passage through the secretory and endocytic pathways, and post-translational modifications regulate their progression through these pathways. All but one of the K(2P) channels possess consensus N-linked glycosylation sites, and here we demonstrate that the conserved putative N-glycosylation site in K(2P)3.1 and K(2P)9.1 is a glycan acceptor site. Patch clamp analysis revealed that disruption of channel glycosylation reduced K(2P)3.1 current, and flow cytometry was instrumental in attributing this to a decreased number of channels on the cell surface. Similar findings were observed when cells were cultured in reduced glucose concentrations. Disruption of N-linked glycosylation has less of an effect on K(2P)9.1, with a small reduction in number of channels on the surface observed, but no functional implications detected. Because nonglycosylated channels appear to pass through the secretory pathway in a manner comparable with glycosylated channels, the evidence presented here suggests that the decreased number of nonglycosylated K(2P)3.1 channels on the cell surface may be due to their decreased stability.

The Influence of Cold Temperature on Cellular Excitability of Hippocampal Networks

The hippocampus plays an important role in short term memory, learning and spatial navigation. A characteristic feature of the hippocampal region is its expression of different electrical population rhythms and activities during different brain states. Physiological fluctuations in brain temperature affect the activity patterns in hippocampus, but the underlying cellular mechanisms are poorly understood. In this work, we investigated the thermal modulation of hippocampal activity at the cellular network level. Primary cell cultures of mouse E17 hippocampus displayed robust network activation upon light cooling of the extracellular solution from baseline physiological temperatures. The activity generated was dependent on action potential firing and excitatory glutamatergic synaptic transmission. Involvement of thermosensitive channels from the transient receptor potential (TRP) family in network activation by temperature changes was ruled out, whereas pharmacological and immunochemical experiments strongly pointed towards the involvement of temperature-sensitive two-pore-domain potassium channels (K2P), TREK/TRAAK family. In hippocampal slices we could show an increase in evoked and spontaneous synaptic activity produced by mild cooling in the physiological range that was prevented by chloroform, a K2P channel opener. We propose that cold-induced closure of background TREK/TRAAK family channels increases the excitability of some hippocampal neurons, acting as a temperature-sensitive gate of network activation. Our findings in the hippocampus open the possibility that small temperature variations in the brain in vivo, associated with metabolism or blood flow oscillations, act as a switch mechanism of neuronal activity and determination of firing patterns through regulation of thermosensitive background potassium channel activity.

Modulation of K2P3.1 (TASK-1), K2P9.1 (TASK-3), and TASK-1/3 heteromer by reactive oxygen species

Reactive oxygen species (ROS) generated by mitochondria or NADPH oxidase have been implicated in the inhibition of K(+) current by hypoxia in chemoreceptor cells. As TASKs are highly active background K(+) channels in these cells, we studied the role of ROS in hypoxia-induced inhibition of TASKs. In HeLa cells expressing TASKs, H(2)O(2) applied to inside-out patches activated TASK-1, TASK-3, and TASK-1/3 heteromer starting at ~16mM. When applied to cell-attached or outside-out patches, 326mM H(2)O(2) did not affect TASK activity. Other K(2P) channels (TREK-1, TREK-2, TASK-2, TALK-1, TRESK) were not affected by H(2)O(2) (tested up to 326mM). A reducing agent (dithiothreitol) and a cysteine-modifying agent (2-aminoethyl methanethiosulfonate hydrobromide) had no effect on basal TASK activity and did not block the H(2)O(2)-induced increase in channel activity. A TASK mutant in which the C-terminus of TASK-3 was replaced with that of TREK-2 showed a normal sensitivity to H(2)O(2). Xanthine/xanthine oxidase mixture used to generate superoxide radical showed no effect on TASK-1, TASK-3, and TASK-1/3 heteromer from either side of the membrane, but it strongly activated TASK-2 from the extracellular side. Acute H(2)O(2) (32-326mM) exposure did not affect hSlo1/b1(BK) expressed in HeLa cells and BK in carotid body glomus cells. In carotid body glomus cells, adrenal cortical cells, and cerebellar granule neurons that show abundant hypoxia-sensitive TASK activity, H(2)O(2) (>16mM) activated the channels only when applied intracellularly, similar to that observed with cloned TASKs. These findings show that ROS do not support or inhibit TASK and BK activity and therefore are unlikely to be the hypoxic signal that causes cell excitation via inhibition of these K(+) channels.

Novel electrophysiological properties of dronedarone: inhibition of human cardiac two-pore-domain potassium (K2P) channels

Dronedarone is currently used for the treatment of paroxysmal and persistent atrial fibrillation (AF). Pharmacological inhibition of cardiac two-pore-domain potassium (K(2P)) channels results in action potential prolongation and has recently been proposed as novel antiarrhythmic strategy. We hypothesized that blockade of human K(2P) channels contributes to the electrophysiological efficacy of dronedarone in AF. Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record K(2P) currents from Xenopus oocytes and Chinese hamster ovary cells. All functional human K(2P) channels were screened for dronedarone sensitivity, revealing significant and concentration-dependent inhibition of cardiac K(2P)2.1 (TREK1; IC(50) = 26.7μM) and K(2P)3.1 channels (TASK1; IC(50) = 18.7μM) with maximum current reduction of 60.3 and 65.5% in oocytes. IC(50) values obtained from mammalian cells yielded 6.1μM (K(2P)2.1) and 5.2μM (K(2P)3.1). The molecular mechanism of action was studied in detail. Dronedarone block affected open and closed channels. K(2P)3.1 currents were reduced in frequency-dependent fashion in contrast to K(2P)2.1. Mutagenesis studies revealed that amino acid residues implicated in K(2P)3.1 drug interactions were not required for dronedarone blockade. The class III antiarrhythmic drug dronedarone targets multiple human cardiac two-pore-domain potassium channels, including atrial-selective K(2P)3.1 currents. K(2P) current inhibition by dronedarone represents a previously unrecognized mechanism of action that extends the multichannel blocking profile of the drug.

Mechanoprotection by Polycystins against Apoptosis Is Mediated through the Opening of Stretch-Activated K2P Channels

How renal epithelial cells respond to increased pressure and the link with kidney disease states remain poorly understood. Pkd1 knockout or expression of a PC2 pathogenic mutant, mimicking the autosomal dominant polycystic kidney disease, dramatically enhances mechanical stress-induced tubular apoptotic cell death. We show the presence of a stretch-activated K(+) channel dependent on the TREK-2 K(2P) subunit in proximal convoluted tubule epithelial cells. Our findings further demonstrate that polycystins protect renal epithelial cells against apoptosis in response to mechanical stress, and this function is mediated through the opening of stretch-activated K(2P) channels. Thus, to our knowledge, we establish for the first time, both in vitro and in vivo, a functional relationship between mechanotransduction and mechanoprotection. We propose that this mechanism is at play in other important pathologies associated with apoptosis and in which pressure or flow stimulation is altered, including heart failure or atherosclerosis.

Age‐related changes in two‐pore domain acid‐sensitive K+ channel expression in rat dorsal root ganglion neurons

1. Two-pore domain K⁺ (K(2P) ) channel expression influences brain development. The K(2P) channels, including two-pore domain acid-sensitive K⁺ (TASK) channels, contribute to the setting of the resting membrane potential of neurons. In addition to neurons in the brain, dorsal root ganglion (DRG) neurons also express K(2P) channels. The aim of the present study was to identify postnatal changes in the expression of TASK channels in DRG neurons. 2. Expression of TASK channels (TASK-1, TASK-2 and TASK-3) was compared between neonatal (postnatal Day (P) 1 or P2) and adult (P120) rat DRG using semiquantitative polymerase chain reaction, western blot analysis, immunostaining and the patch-clamp technique. 3. In adult (P120) rat DRG, expression of TASK-2 mRNA and protein was downregulated, whereas TASK-3 mRNA and protein expression was upregulated. There were no consistent changes in TASK-1 mRNA and protein expression. Single-channel recordings showed very low TASK-2- and TASK-3-like channel expression in P1-P2 DRG neurons (∼10% in TASK-2 and ∼3% in TASK-3). In P120 DRG, there was a reduction in the detection of TASK-2-like channels, whereas the detection of TASK-3-like channels increased. 4. These results show that TASK-2 and TASK-3 mRNA and protein expression undergoes age-related changes in DRG neurons, indicating that TASK-2 and TASK-3 channels are likely to contribute to the setting of the resting membrane potential of DRG neurons in neonates and adults, separately or together, during DRG development.

Generation of a two-photon state from a quantum dot in a microcavity

We propose and characterize a two-photon (2P) source that emits in a highly polarized, monochromatic and directional beam, realized by means of a quantum dot embedded in a linearly polarized cavity. In our scheme, the cavity frequency is tuned to half the frequency of the biexciton (two excitons with opposite spins) and largely detuned from the excitons thanks to the large biexciton binding energy. We show how the emission can be Purcell enhanced by several orders of magnitude into the 2P channel for available experimental systems.

Reduction of breast cancer cell migration via up‐regulation of TASK‐3 two‐pore domain K+ channel

Many kinds of K(+) channels are expressed in a variety of cells, including cancer cells. However, only a small amount of research has explored the relationship between voltage-independent K(+) channels and breast cancer. This study was performed to investigate whether changes in two-pore domain K(+) (K(2P) ) channel expression levels are related to the migration of human breast cancer cells. K(2P) channel gene/protein expression levels were compared between MCF-7 (a non-invasive cell) and MDA-MB-231 (an invasive cell) using reverse transcriptase (RT)-polymerase chain reaction (PCR), real-time PCR, Western blotting and immunocytochemistry. The relationship between K(2P) channel expression level and cell migration was analysed using gene overexpression and knock-down techniques. Functional expression of TASK-3 in MCF-7 and MDA-MB-231 cells was recorded using patch-clamp technique. Of K(2P) channels, TASK-3 mRNA and protein were highly expressed in MCF-7 cells compared with those in MDA-MB-231 cells. Overexpression of TASK-3 in breast cancer cells reduced migration and invasion, whereas silencing of TASK-3 increased the migration and invasion. The TASK-3 expression level was decreased by phorbol myristate acetate (PMA), a PKC activator. PMA also enhanced the cell migration in MDA-MB-231 cells. These results show that an increase in TASK-3 expression levels, which could be modulated by PKC activation, reduces cell migration/invasion in breast cancer cells and suggest that modulation of TASK-3 expression may regulate metastasis of breast cancer cells.