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V. Frouin - One of the best experts on this subject based on the ideXlab platform.
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Multivariate Haplotype Analysis Of 96 Sulci Opening For 15,612 UK-Biobank Sujects
2019 IEEE 16th International Symposium on Biomedical Imaging (ISBI 2019), 2019Co-Authors: S. Karkar, A. Gloaguen, Le Y. Guen, M. Pierre-jean, C. Dandine-roulland, Le E. Floch, C. Philippe, A. Tenenhaus, V. FrouinAbstract:Imaging genetic studies of large control cohorts such as UK Biobank enable to assess the range of normal variations in brain structures. Previous studies by our group have shown that the width of several cortical sulci is associated with a variant in the upstream region of KCNK2 gene even if this effect is corrected with age. Here we propose to analyze in a multivariate setup the associations between sets of genetic variants and multiple sulci widths. The genetic variants we consider are sets of SNPs of known phase called haplotypes, taken from the upstream region of KCNK2 gene. To the best of our knowledge, multivariate analysis in imaging genetics has never been used in haplotype studies. Our method was able to recover the expected association signal and uncover new associations between imaging data and genetic variants.
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ISBI - Multivariate Haplotype Analysis Of 96 Sulci Opening For 15,612 UK-Biobank Sujects
2019 IEEE 16th International Symposium on Biomedical Imaging (ISBI 2019), 2019Co-Authors: S. Karkar, A. Gloaguen, M. Pierre-jean, C. Dandine-roulland, C. Philippe, A. Tenenhaus, Y. Le Guen, E. Le Floc'h, V. FrouinAbstract:Imaging genetic studies of large control cohorts such as UK Biobank enable to assess the range of normal variations in brain structures. Previous studies by our group have shown that the width of several cortical sulci is associated with a variant in the upstream region of KCNK2 gene even if this effect is corrected with age. Here we propose to analyze in a multivariate setup the associations between sets of genetic variants and multiple sulci widths. The genetic variants we consider are sets of SNPs of known phase called haplotypes, taken from the upstream region of KCNK2 gene. To the best of our knowledge, multivariate analysis in imaging genetics has never been used in haplotype studies. Our method was able to recover the expected association signal and uncover new associations between imaging data and genetic variants.
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eqtl of KCNK2 regionally influences the brain sulcal widening evidence from 15 597 uk biobank participants with neuroimaging data
Brain Structure & Function, 2019Co-Authors: Yann Le Guen, C. Philippe, D Riviere, Herve Lemaitre, Antoine Grigis, Clara Fischer, Ghislaine Dehaenelambertz, Jeanfrancois Mangin, V. FrouinAbstract:The grey and white matter volumes are known to reduce with age. This cortical shrinkage is visible on magnetic resonance images and is conveniently identified by the increased volume of cerebrospinal fluid in the sulci between two gyri. Here, we replicated this finding using the UK Biobank dataset and studied the genetic influence on these cortical features of aging. We divided all individuals genetically confirmed of British ancestry into two sub-cohorts (12,162 and 3435 subjects for discovery and replication samples, respectively). We found that the heritability of the sulcal opening ranges from 15 to 45% (SE = 4.8%). We identified 4 new loci that contribute to this opening, including one that also affects the sulci grey matter thickness. We identified the most significant variant (rs864736) on this locus as being an expression quantitative trait locus (eQTL) for the KCNK2 gene. This gene regulates the immune-cell into the central nervous system (CNS) and controls the CNS inflammation, which is implicated in cortical atrophy and cognitive decline. These results expand our knowledge of the genetic contribution to cortical shrinking and promote further investigation into these variants and genes in pathological context such as Alzheimer’s disease in which brain shrinkage is a key biomarker.
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eqtl of KCNK2 regionally influences the brain sulcal widening evidence from 15 597 uk biobank participants with neuroimaging data
bioRxiv, 2018Co-Authors: Yann Le Guen, C. Philippe, D Riviere, Herve Lemaitre, Antoine Grigis, Clara Fischer, Ghislaine Dehaenelambertz, Jeanfrancois Mangin, V. FrouinAbstract:The grey and white matter volumes are known to reduce with age. This cortical shrinkage is visible on magnetic resonance images and is conveniently identified by the increased volume of cerebrospinal fluid in the sulci between two gyri. Here, we replicated this finding using the UK Biobank dataset and studied the genetic influence on these cortical features of aging. We divided all individuals genetically confirmed of British ancestry into two sub-cohorts (12,162 and 3,435 subjects for discovery and replication samples, respectively). We found that the heritability of the sulcal opening ranges from 15 to 45% (s.e.= 4.8%). We identified 4 new loci that contribute to this opening, including one that also affects the sulci grey matter thickness. We identified the most significant variant (rs864736) on this locus as being an expression quantitative trait locus (eQTL) for the KCNK2 gene. This gene regulates the immune-cell into the central nervous system (CNS) and controls the CNS inflammation, which is implicated in cortical atrophy and cognitive decline. These results expand our knowledge of the genetic contribution to cortical shrinking and promote further investigation into these variants and genes in pathological context such as Alzheimer′s disease in which brain shrinkage is a key biomarker.
A. Innamaa - One of the best experts on this subject based on the ideXlab platform.
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Expression and effects of modulation of the K2P potassium channels TREK-1 (KCNK2) and TREK-2 (KCNK10) in the normal human ovary and epithelial ovarian cancer
Clinical and Translational Oncology, 2013Co-Authors: A. Innamaa, L. Jackson, V. Asher, G. Schalkwyk, A. Warren, A. Keightley, A. Bali, H. Sowter, R. KhanAbstract:Purpose Aberrant expression of potassium (K^+) channels contributes to cancer cell proliferation and apoptosis, and K^+ channel blockers can inhibit cell proliferation. TREK-1 and -2 belong to the two-pore domain (K2P) superfamily. We report TREK-1 and -2 expression in ovarian cancer and normal ovaries, and the effects of TREK-1 modulators on cell proliferation and apoptosis. Methods The cellular localisation of TREK-1 and -2 was investigated by immunofluorescence in SKOV-3 and OVCAR-3 cell lines and in cultured ovarian surface epithelium and cancer. Channel expression in normal ovaries and cancer was quantified by western blotting. Immunohistochemical analysis demonstrated the association between channel expression and disease prognosis, stage, and grade. TREK-1 modulation of cell proliferation in the cell lines was investigated with the MTS-assay and the effect on apoptosis determined using flow cytometry. Results Expression was identified in both cell lines, ovarian cancer ( n = 22) and normal ovaries ( n = 6). IHC demonstrated positive staining for TREK-1 and -2 in 95.7 % of tumours ( n = 69) and 100 % of normal ovaries ( n = 9). A reduction in cell proliferation ( P
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expression and effects of modulation of the k2p potassium channels trek 1 KCNK2 and trek 2 kcnk10 in the normal human ovary and epithelial ovarian cancer
Clinical & Translational Oncology, 2013Co-Authors: A. Innamaa, L. Jackson, V. Asher, G. Schalkwyk, A. Keightley, A. Bali, H. Sowter, Averil Y Warren, Raheela N KhanAbstract:Aberrant expression of potassium (K+) channels contributes to cancer cell proliferation and apoptosis, and K+ channel blockers can inhibit cell proliferation. TREK-1 and -2 belong to the two-pore domain (K2P) superfamily. We report TREK-1 and -2 expression in ovarian cancer and normal ovaries, and the effects of TREK-1 modulators on cell proliferation and apoptosis. The cellular localisation of TREK-1 and -2 was investigated by immunofluorescence in SKOV-3 and OVCAR-3 cell lines and in cultured ovarian surface epithelium and cancer. Channel expression in normal ovaries and cancer was quantified by western blotting. Immunohistochemical analysis demonstrated the association between channel expression and disease prognosis, stage, and grade. TREK-1 modulation of cell proliferation in the cell lines was investigated with the MTS-assay and the effect on apoptosis determined using flow cytometry. Expression was identified in both cell lines, ovarian cancer (n = 22) and normal ovaries (n = 6). IHC demonstrated positive staining for TREK-1 and -2 in 95.7 % of tumours (n = 69) and 100 % of normal ovaries (n = 9). A reduction in cell proliferation (P < 0.05) was demonstrated at 96 h in SKOV-3 and OVCAR-3 cells incubated TREK-1 modulating agents. Curcumin caused a significant reduction in early apoptosis in SKOV-3 (P < 0.001) and OVCAR-3 (P < 0.0001) cells and a significant increase in late apoptosis in SKOV-3 (P < 0.01) and OVCAR-3 cells (P < 0.0001). TREK-1 and -2 are expressed in normal ovaries and ovarian cancer. TREK-1 modulators have a significant effect on cell proliferation and apoptosis. We propose investigation of the therapeutic potential of TREK-1 blockers is warranted.
Noam Zilberberg - One of the best experts on this subject based on the ideXlab platform.
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Molecular Mechanisms Underlying Membrane Potential-Mediated Regulation of Neuronal K2P2.1 Channels
Biophysical Journal, 2020Co-Authors: Yifat Segal-hayoun, Asi Cohen, Noam ZilberbergAbstract:The activity of background K2P channels adjusts the resting membrane potential to enable plasticity of excitable cells. Here we have studied the regulation of neuronal human K2P2.1 (KCNK2, TREK-1) channel activity by resting membrane potential. When heterologously expressed in Xenopus laevis oocytes, K2P2.1 currents gradually increased several fold at hyperpolarizing potentials and declined several fold at depolarizing potentials, with a midpoint potential of −60 mV. As K2P channels are not equipped with an integral voltage sensor, we sought extrinsic cellular components that could convert changes in the membrane electrical field to cellular activity that would indirectly modify K2P2.1 currents. K2P2.1 voltage sensitivity was found not to be mediated by the activity of either voltage activated calcium channels, the Xenopus voltage sensitive proton channel (Xl-Hv) or the Xenopus voltage sensor-containing phosphatase (Xl-VSP). On the other hand, we report that membrane depolarization activated the Gq protein-coupled receptor pathway, in the apparent absence of ligand, resulting in phosphatidylinositol-4,5-bisphosphate (PIP2) depletion through the action of phospholipase C. Our results suggest a novel mechanism in which an indirect pathway confers membrane potential regulation onto channels that are not intrinsically voltage-sensitive to enhance regulation of neuronal excitability levels. The ability of these proteins to operate without any external ligand enhances plasticity at the single cell level, independent of higher regulatory pathways at the tissue or even the organism levels.
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A regulatory domain in the K2P2.1 (TREK-1) carboxyl-terminal allows for channel activation by monoterpenes
bioRxiv, 2020Co-Authors: Eden Arazi, Galit Blecher, Noam ZilberbergAbstract:Abstract Potassium K2P (‘leak’) channels conduct current across the entire physiological voltage range and carry leak or ‘background’ currents that are, in part, time- and voltage-independent. K2P2.1 channels (i.e., TREK-1, KCNK2) are highly expressed in excitable tissues, where they play a key role in the cellular mechanisms of neuroprotection, anesthesia, pain perception, and depression. Here, we report for the first time that human K2P2.1 channel activity is regulated by monoterpenes (MTs). We found that cyclic, aromatic monoterpenes containing a phenol moiety, such as carvacrol, thymol and 4-IPP had the most profound effect on current flowing through the channel (up to a 6-fold increase). By performing sequential truncation of the carboxyl-terminal domain of the channel and testing the activity of several channel regulators, we identified two distinct regulatory domains within this portion of the protein. One domain, as previously reported, was needed for regulation by arachidonic acid, anionic phospholipids and temperature changes. Within a second domain, a triple arginine residue motif (R344-346), an apparent PIP2-binding site, was found to be essential for regulation by holding potential changes and important for regulation by monoterpenes.
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Molecular mechanisms underlying membrane-potential-mediated regulation of neuronal K2P2.1 channels.
Molecular and Cellular Neuroscience, 2009Co-Authors: Yifat Segal-hayoun, Asi Cohen, Noam ZilberbergAbstract:Abstract The activity of background K 2P channels adjusts the resting membrane potential to enable plasticity of excitable cells. Here we have studied the regulation of neuronal K 2P 2.1 (KCNK2, TREK-1) channel activity by resting membrane potential. When heterologously expressed, K 2P 2.1 currents gradually increased at hyperpolarizing potentials and declined at depolarizing potentials, with a midpoint potential of − 60 mV. As K 2P channels are not equipped with an integral voltage sensor, we sought extrinsic cellular components that could convert changes in the membrane electrical field to cellular activity that would indirectly modify K 2P 2.1 currents. We propose that membrane depolarization activated the Gq protein-coupled receptor pathway, in the apparent absence of ligand, resulting in phosphatidylinositol-4,5-bisphosphate (PIP 2 ) depletion through the action of phospholipase C. Our results suggest a novel mechanism in which an indirect pathway confers membrane potential regulation onto channels that are not intrinsically voltage sensitive to enhance regulation of neuronal excitability levels.
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Two Distinct Molecular Mechanisms Underlie pH Sensitivity of the Human Potassium Leak Channel K2P2.1
Biophysical Journal, 2009Co-Authors: Asi Cohen, Noam ZilberbergAbstract:The mammalian K2P2.1 potassium channel (TREK-1, KCNK2) is highly expressed in excitable tissues, where it plays a key role in the cellular mechanisms of neuroprotection, anaesthesia, pain perception and depression. Here, we report that external acidification, within the physiological range, strongly inhibits the human K2P2.1 channel in two distinct time scales. We have identified two histidine residues (i.e., H87 and H141), located in the first external loop of the channel, which govern the fast response of the channel to external pH (in the time scale of seconds). We demonstrate that these residues are within physical proximity to glutamate 84, homologous to Shaker E418, KcsA E51 and KCNK0 E28 residues, all previously reported to stabilize the outer pore gate in the open conformation by forming hydrogen bonds with pore-adjacent residues. We thus propose a novel mechanism for pH sensing in which protonation of H141 and H87 generates a local positive charge that serves to draw E84 away from its natural interactions, facilitating the collapse of the selectivity filter region, a mechanism which resembles C-type gating of voltage dependent potassium channels. In accordance with this proposed mechanism, the proton-mediated effect was inhibited by external potassium ions, modified the channel's ion selectivity and was enhanced by a mutation, S164Y, known to accelerate C-type gating. In addition, we show that the slow regulatory effect (in the time scale of minutes) is mediated by proton-sensitive G-protein coupled receptors (GPCRs), which activated phospholipase C via the Gq pathway. We demonstrate that three residues within the C-terminal of K2P2.1 mediate the channel's response to the observed GPCRs activation by acidic pH.Taken together, our results highlight the physiological importance of human K2P2.1 channels as sensors of extracellular pH in the central nervous system.
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Pain-associated signals, acidosis and lysophosphatidic acid, modulate the neuronal K2P2.1 channel
Molecular and Cellular Neuroscience, 2008Co-Authors: Asi Cohen, Revital Sagron, Erez Somech, Yifat Segal-hayoun, Noam ZilberbergAbstract:Abstract Pain is a physiological state promoting protective responses to harmful episodes. However, pain can become pathophysiological and become a chronic disruptive condition, damaging quality of life. The mammalian K2P2.1 (KCNK2, TREK-1) channel, expressed in sensory neurons of the dorsal root ganglia, was previously identified as a polymodal molecular sensor involved in pain perception. Here, we report that two pain-associated signals, external acidosis and lysophosphatidic acid (LPA), known to rise during injury, inflammation and cancer, profoundly down-modulate human K2P2.1 activity. The pH regulatory effect was mediated by activation of proton-sensitive G-protein coupled receptors and phospholipase C. Physiological concentrations of LPA overcame the effects of known K2P2.1 activators, such as arachidonic acid, lysophosphatidylcholine and temperature, by activating cell-surface receptors stimulating the Gq pathway. Furthermore, we identified three K2P2.1 carboxy-terminal residues that mediate both pH and LPA regulatory effects. Our results highlight the important role of K2P2.1 channels as receptors for mediators known to cause nociception.
Eric Honoré - One of the best experts on this subject based on the ideXlab platform.
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Cross-talk between the mechano-gated K2P channel TREK-1 and the actin cytoskeleton.
EMBO Reports, 2020Co-Authors: Inger Lauritzen, Jean Chemin, Michel Lazdunski, Eric Honoré, Martine Jodar, Amanda PatelAbstract:TREK-1 (KCNK2) is a K2P channel that is highly expressed in fetal neurons. This K+ channel is opened by a variety of stimuli, including membrane stretch and cellular lipids. Here, we show that the expression of TREK-1 markedly alters the cytoskeletal network and induces the formation of actin- and ezrin-rich membrane protrusions. The genetic inactivation of TREK-1 significantly alters the growth cone morphology of cultured embryonic striatal neurons. Cytoskeleton remodelling is crucially dependent on the protein kinase A phosphorylation site S333 and the interactive proton sensor E306, but is independent of channel permeation. Conversely, the actin cytoskeleton tonically represses TREK-1 mechano-sensitivity. Thus, the dialogue between TREK-1 and the actin cytoskeleton might influence both synaptogenesis and neuronal electrogenesis.
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The TREK two P domain K+ channels
The Journal of Physiology, 2020Co-Authors: Amanda Patel, Eric HonoréAbstract:K+ channels form the most diverse family of ion channels with more than 70 genes cloned in humans. They can be broadly subdivided into three structural classes made of two, four or six transmembrane segments (TMS) (Patel & Honore, 2001a). All K+ channels can be recognized by the presence of a conserved motif called the P domain (the pore-forming region), which is part of the K+ conduction pathway. The two TMS and six TMS classes contain a single P domain while the class of four TMS subunits contains two P domains in tandem. Functional K+ channels are tetramers of pore-forming subunits for the two and six TMS classes and probably dimers in the case of the four TMS class (Fig. 1). Figure 1 TREK channels are opened by a variety of physical (stretch, acidosis and heat) and chemical stimuli (polyunsaturated fatty acids, lysophospholipids and volatile anaesthetics) and are regulated by phosphorylation The family of mammalian 4TMS/2P K+ channel subunits has increased to 14 members (Patel & Honore, 2001a). These subunits share the same structural motif, but low sequence identity is found outside the P domains. TREK-1 (KCNK2), TREK-2 (KCNK10) and TRAAK (KCNK4) subunits share the closest sequence identity ranging from 63 to 78 %, and form a structural as well as a functional subgroup. Human TREK channels are highly expressed in the central and peripheral nervous systems, but are absent from the heart. TREK channels are opened by a variety of physical and chemical stimuli (Patel & Honore, 2001a). TREK channel activity is elicited by increasing mechanical pressure applied to the cell membrane (Patel & Honore, 2001a; Patel et al. 2001). At the whole-cell level, TREK-1 is modulated by cellular volume. Acidosis converts TREK mechano-gated channels into constitutively active channels. Finally, heat gradually and reversibly opens TREK-1 with an exceptional Q10 value of 7. Deletional analysis demonstrates that the carboxy terminus, but not the amino terminus and the extracellular M1P1 loop, is critical for activation of TREK-1 by stretch, intracellular acidosis and heat. TREK channels are reversibly opened by anionic polyunsaturated fatty acids including arachidonic acid. The activation is either directly on the channel protein or via a membrane effect (Patel et al. 2001). Lysophospholipids containing large polar heads are additional potent openers. TREK channels are the target for volatile general anaesthetics including halothane and isoflurane (Patel & Honore, 2001b). Opening of these channels by inhalational anaesthetics induces cell hyperpolarization and may contribute to general anaesthesia (Patel & Honore, 2001b). Chemical activation of TREK-1 is also critically dependent on the carboxy terminal domain (Patel & Honore, 2001a,b; Patel et al. 2001). TREK channels are additionally regulated by the neurotransmitter/cAMP/PKA pathway (Patel & Honore, 2001a). For instance, opening of TREK-1 by lipids is reversed by protein kinase A stimulation. Protein kinase A-mediated phosphorylation of Ser333 in the carboxy terminus mediates TREK-1 closing. TREK-1 activity is also inhibited by the protein kinase C pathway, although the phosphorylation site remains to be identified. The biophysical and pharmacological properties of TREK channels resemble those of the Aplysia S-type K+ channel (Belardetti & Siegelbaum, 1988; Patel & Honore, 2001a) (Fig. 1). The S channel is responsible for the control of presynaptic facilitation of transmitter release that underlies behavioural sensitization, a simple form of learning and memory. Considering that TREK channels are highly expressed in the hippocampus and the cerebral cortex, they may play a significant role in cognition (Patel & Honore, 2001a). In this issue of The Journal of Physiology, Gu et al. identify two splice variants of TREK-2 differing in their 5′ untranslated region and in the coding region for the first 17 amino acids. These splice variants are differentially expressed in the brain and the kidney. Interestingly, the brain splice variant gives 2.5-fold larger currents than the kidney splice variant when transfected in human embryonic kidney cells. These results suggest a novel role for the amino terminus of TREK-2 in regulating targeting to the cell surface, channel turnover and/or interaction with auxiliary proteins. Cell-specific alternative splicing may thus be important to tune the functional expression of the 2P domain K+ channels.
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Multiple modalities converge on a common gate to control K2P channel function
The EMBO Journal, 2011Co-Authors: Sviatoslav N. Bagriantsev, Kimberly A. Clark, Eric Honoré, Rémi Peyronnet, Daniel L. MinorAbstract:Members of the K2P potassium channel family regulate neuronal excitability and are implicated in pain, anaesthetic responses, thermosensation, neuroprotection, and mood. Unlike other potassium channels, K2Ps are gated by remarkably diverse stimuli that include chemical, thermal, and mechanical modalities. It has remained unclear whether the various gating inputs act through separate or common channel elements. Here, we show that protons, heat, and pressure affect activity of the prototypical, polymodal K2P, K2P2.1 (KCNK2/TREK-1), at a common molecular gate that comprises elements of the pore-forming segments and the N-terminal end of the M4 transmembrane segment. We further demonstrate that the M4 gating element is conserved among K2Ps and is employed regardless of whether the gating stimuli are inhibitory or activating. Our results define a unique gating mechanism shared by K2P family members and suggest that their diverse sensory properties are achieved by coupling different molecular sensors to a conserved core gating apparatus.
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Protons, Heat, and Mechanical Force Act Through a Common Gate to Control K2P Channel Function
Biophysical Journal, 2011Co-Authors: Sviatoslav N. Bagriantsev, Eric Honoré, Rémi Peyronnet, Daniel L. MinorAbstract:Members of the K2P potassium channel family are key regulators of cell excitability and are implicated in pain, anesthetic responses, thermosensation, neuroprotection, and mood. Unlike other potassium channel families, K2P channels are gated by remarkably diverse stimuli that include chemical, thermal, and mechanical modalities. It has remained unclear whether the various gating inputs act through separate or common channel elements. Here, we show that protons, heat, and pressure affect the activity of the prototypical, polymodal K2P channel, K2P2.1 (KCNK2/TREK-1), at a common molecular gate that comprises extracellular elements of the pore-forming segments and part of the putative fourth transmembrane helix, M4, that is proximal to the extracellular end. We further demonstrate that the functional importance of the M4 gating element is conserved across the K2P family, regardless of whether the gating stimuli are inhibitory or activating. Taken together, our results highlight a unique gating mechanism shared by K2P channels and suggest that the diverse sensory properties of K2P channels are achieved by coupling different molecular sensors to a conserved core gating apparatus comprising the selectivity filter and M4.
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Regulation of the Mechano-Gated K2P Channel TREK-1 by Membrane Phospholipids.
Current Topics in Membranes, 2007Co-Authors: Jean Chemin, Amanda Patel, Michel Lazdunski, Patrick Delmas, Frederick Sachs, Eric HonoréAbstract:Publisher Summary This chapter discusses the regulation of the mechano-gated K2P channel, TREK-1 by membrane phospholipids. TREK-1 (KCNK2 or K2P2.1) is a polymodal K+ channel that is activated by membrane stretch, intracellular acidosis, heat, and cellular lipids, such as arachidonic acid (AA). Phospholipids, including PIP2, exert a dual dose-dependent effect on TREK-1. Low concentrations transform the mechanogated K+ channel TREK-1 into a leak K+ channel. The phospholipid-sensing domain is a positively charged cluster in the proximal C-terminal domain. This region also encompasses the proton sensor E306 that is required for the activation of TREK-1 by cytosolic acidosis. Protonation of E306 increases channel-phospholipid interaction leading to TREK-1 opening without direct-mechanical stimulation. At higher concentrations, intracellular phospholipids inhibit channel activation by stretch, intracellular acidosis, and AA. Binding endogenous negative inner leaflet phospholipids with polylysine reduces the inhibition and reveals channel stimulation by exogenous intracellular phospholipids. Both stimulatory and inhibitory effects are observed with phosphatidylinositol (PI), phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidic acid (PA), but not diacylglycerol (DG), suggesting that the phosphate at position 3 is required, although the net charge is not critical. Membrane phospholipids, including PIP2, are major regulators of TREK-1 channel activity.
Raheela N Khan - One of the best experts on this subject based on the ideXlab platform.
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expression and effects of modulation of the k2p potassium channels trek 1 KCNK2 and trek 2 kcnk10 in the normal human ovary and epithelial ovarian cancer
Clinical & Translational Oncology, 2013Co-Authors: A. Innamaa, L. Jackson, V. Asher, G. Schalkwyk, A. Keightley, A. Bali, H. Sowter, Averil Y Warren, Raheela N KhanAbstract:Aberrant expression of potassium (K+) channels contributes to cancer cell proliferation and apoptosis, and K+ channel blockers can inhibit cell proliferation. TREK-1 and -2 belong to the two-pore domain (K2P) superfamily. We report TREK-1 and -2 expression in ovarian cancer and normal ovaries, and the effects of TREK-1 modulators on cell proliferation and apoptosis. The cellular localisation of TREK-1 and -2 was investigated by immunofluorescence in SKOV-3 and OVCAR-3 cell lines and in cultured ovarian surface epithelium and cancer. Channel expression in normal ovaries and cancer was quantified by western blotting. Immunohistochemical analysis demonstrated the association between channel expression and disease prognosis, stage, and grade. TREK-1 modulation of cell proliferation in the cell lines was investigated with the MTS-assay and the effect on apoptosis determined using flow cytometry. Expression was identified in both cell lines, ovarian cancer (n = 22) and normal ovaries (n = 6). IHC demonstrated positive staining for TREK-1 and -2 in 95.7 % of tumours (n = 69) and 100 % of normal ovaries (n = 9). A reduction in cell proliferation (P < 0.05) was demonstrated at 96 h in SKOV-3 and OVCAR-3 cells incubated TREK-1 modulating agents. Curcumin caused a significant reduction in early apoptosis in SKOV-3 (P < 0.001) and OVCAR-3 (P < 0.0001) cells and a significant increase in late apoptosis in SKOV-3 (P < 0.01) and OVCAR-3 cells (P < 0.0001). TREK-1 and -2 are expressed in normal ovaries and ovarian cancer. TREK-1 modulators have a significant effect on cell proliferation and apoptosis. We propose investigation of the therapeutic potential of TREK-1 blockers is warranted.