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https://www.readbyqxmd.com/read/29772789/downregulation-of-the-s1p-transporter-spinster-homology-protein-2-spns2-exerts-an-anti-fibrotic-and-anti-inflammatory-effect-in-human-renal-proximal-tubular-epithelial-cells
#1
Olivier Blanchard, Bisera Stepanovska, Manuel Starck, Martin Erhardt, Isolde Römer, Dagmar Meyer Zu Heringdorf, Josef Pfeilschifter, Uwe Zangemeister-Wittke, Andrea Huwiler
Sphingosine kinase (SK) catalyses the formation of sphingosine 1-phosphate (S1P), which acts as a key regulator of inflammatory and fibrotic reactions, mainly via S1P receptor activation. Here, we show that in the human renal proximal tubular epithelial cell line HK2, the profibrotic mediator transforming growth factor β (TGFβ) induces SK-1 mRNA and protein expression, and in parallel, it also upregulates the expression of the fibrotic markers connective tissue growth factor (CTGF) and fibronectin. Stable downregulation of SK-1 by RNAi resulted in the increased expression of CTGF, suggesting a suppressive effect of SK-1-derived intracellular S1P in the fibrotic process, which is lost when SK-1 is downregulated...
May 17, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29737974/ca2-calmodulin-dependent-protein-kinase-ii-camkii-increases-small-conductance-ca2-activated-k-current-in-patients-with-chronic-atrial-fibrillation
#2
Xuehui Fan, Yiyan Yu, Huan Lan, Xianhong Ou, Lijie Yang, Tao Li, Jiming Cao, Xiaorong Zeng, Miaoling Li
BACKGROUND Increased small-conductance Ca2+-activated K+ current (SK), abnormal intracellular Ca2+ handling, and enhanced expression and activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) have been found in clinical and/or experimental models of atrial fibrillation (AF), but the cumulative effect of these phenomena and their mechanisms in AF are still unclear. This study aimed to test the hypothesis that CaMKII increases SK current in human chronic AF. MATERIAL AND METHODS Right atrial appendage tissues from patients with either sinus rhythm (SR) or AF and neonatal rat atrial myocytes were used...
May 8, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29724949/activation-mechanism-of-a-human-sk-calmodulin-channel-complex-elucidated-by-cryo-em-structures
#3
Chia-Hsueh Lee, Roderick MacKinnon
Small-conductance Ca2+ -activated K+ (SK) channels mediate neuron excitability and are associated with synaptic transmission and plasticity. They also regulate immune responses and the size of blood cells. Activation of SK channels requires calmodulin (CaM), but how CaM binds and opens SK channels has been unclear. Here we report cryo-electron microscopy (cryo-EM) structures of a human SK4-CaM channel complex in closed and activated states at 3.4- and 3.5-angstrom resolution, respectively. Four CaM molecules bind to one channel tetramer...
May 4, 2018: Science
https://www.readbyqxmd.com/read/29719463/compound-k-induced-apoptosis-via-endoplasmic-reticulum-ca-2-release-through-ryanodine-receptor-in-human-lung-cancer-cells
#4
Dong-Hyun Shin, Dong-Gyu Leem, Ji-Sun Shin, Joo-Il Kim, Kyung-Tack Kim, Sang Yoon Choi, Myung-Hee Lee, Jung-Hye Choi, Kyung-Tae Lee
Background: Extended endoplasmic reticulum (ER) stress may initiate apoptotic pathways in cancer cells, and ER stress has been reported to possibly increase tumor death in cancer therapy. We previously reported that caspase-8 played an important role in compound K-induced apoptosis via activation of caspase-3 directly or indirectly through Bid cleavage, cytochrome c release, and caspase-9 activation in HL-60 human leukemia cells. The mechanisms leading to apoptosis in A549 and SK-MES-1 human lung cancer cells and the role of ER stress have not yet been understood...
April 2018: Journal of Ginseng Research
https://www.readbyqxmd.com/read/29677462/ondansetron-blocks-wildtype-and-p-f503l-variant-small-conductance-calcium-activated-potassium-channels
#5
Jum-Suk Ko, Shuai Guo, Jonathan Hassel, Patricia Celestino-Soper, Ty C Lynnes, James E Tisdale, James J Zheng, Stanley E Taylor, Tatiana Foroud, Michael D Murray, Richard J Kovacs, Xiaochun Li, Shien-Fong Lin, Zhenhui Chen, Matteo Vatta, Peng-Sheng Chen, Michael Rubart
The apamin-sensitive, small conductance, calcium-activated potassium (SK) current ( IKAS ) is encoded by KCNN genes. IKAS importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that IKAS inhibition contributes to drug-induced long QT (diLQT) syndrome, we (1) screened for KCNN variants among patients with diLQT, (2) determined the properties of heterologously expressed wildtype and variant KCNN channels, and (3) determined if the 5-HT3 receptor antagonist ondansetron blocks IKAS ...
April 20, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29651007/small-conductance-ca-2-activated-k-channels-insights-into-their-roles-in-cardiovascular-disease
#6
REVIEW
Mingxia Gu, Yanrong Zhu, Xiaorong Yin, Dai-Min Zhang
Life-threatening malignant arrhythmias in pathophysiological conditions can increase the mortality and morbidity of patients with cardiovascular diseases. Cardiac electrical activity depends on the coordinated propagation of excitatory stimuli and the generation of action potentials in cardiomyocytes. Action potential formation results from the opening and closing of ion channels. Recent studies have indicated that small-conductance calcium-activated potassium (SK) channels play a critical role in cardiac repolarization in pathophysiological but not normal physiological conditions...
April 13, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29576321/an-intracellular-allosteric-modulator-binding-pocket-in-sk2-ion-channels-is-shared-by-multiple-chemotypes
#7
Lily T-Y Cho, Aristos J Alexandrou, Rubben Torella, John Knafels, Jake Hobbs, Toni Taylor, Alex Loucif, Agnieszka Konopacka, Sigourney Bell, Edward B Stevens, Jay Pandit, Reto Horst, Jane M Withka, David C Pryde, Shenping Liu, Gareth T Young
Small conductance potassium (SK) ion channels define neuronal firing rates by conducting the after-hyperpolarization current. They are key targets in developing therapies where neuronal firing rates are dysfunctional, such as in epilepsy, Parkinson's, and amyotrophic lateral sclerosis (ALS). Here, we characterize a binding pocket situated at the intracellular interface of SK2 and calmodulin, which we show to be shared by multiple small-molecule chemotypes. Crystallization of this complex revealed that riluzole (approved for ALS) and an analog of the anti-ataxic agent (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidin-4-yl]-amine (CyPPA) bind to and allosterically modulate via this site...
March 19, 2018: Structure
https://www.readbyqxmd.com/read/29549309/coupling-of-sk-channels-l-type-ca-2-channels-and-ryanodine-receptors-in-cardiomyocytes
#8
Xiao-Dong Zhang, Zana A Coulibaly, Wei Chun Chen, Hannah A Ledford, Jeong Han Lee, Padmini Sirish, Gu Dai, Zhong Jian, Frank Chuang, Ingrid Brust-Mascher, Ebenezer N Yamoah, Ye Chen-Izu, Leighton T Izu, Nipavan Chiamvimonvat
Small-conductance Ca2+ -activated K+ (SK) channels regulate the excitability of cardiomyocytes by integrating intracellular Ca2+ and membrane potentials on a beat-to-beat basis. The inextricable interplay between activation of SK channels and Ca2+ dynamics suggests the pathology of one begets another. Yet, the exact mechanistic underpinning for the activation of cardiac SK channels remains unaddressed. Here, we investigated the intracellular Ca2+ microdomains necessary for SK channel activation. SK currents coupled with Ca2+ influx via L-type Ca2+ channels (LTCCs) continued to be elicited after application of caffeine, ryanodine or thapsigargin to deplete SR Ca2+ store, suggesting that LTCCs provide the immediate Ca2+ microdomain for the activation of SK channels in cardiomyocytes...
March 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29537926/changes-in-potassium-channel-modulation-may-underlie-afterhyperpolarization-plasticity-in-oxytocin-neurons-during-late-pregnancy
#9
Lie Wang, Giri Kumar Chandaka, Robert C Foehring, Joseph C Callaway, William E Armstrong
Oxytocin (OT) neurons exhibit larger afterhyperpolarizations (AHPs) following spike trains during pregnancy and lactation, when these neurons burst and release more OT. Calcium-dependent AHPs mediated by SK channels show this plasticity, and are reduced when the channel is phosphorylated by casein kinase 2 (CK2), and increased when dephosphorylated by protein phosphatase 2A (PP2A), by altering Ca2+ sensitivity. We compared AHP currents in supraoptic OT neurons after CK2 inhibition with 4,5,6,7-tetrabromobenzotriazole (TBB), or PP1-PP2A inhibition with okadaic acid (OA) focusing on the peak current at 100 ms representing the SK-mediated, medium AHP (ImAHP )...
March 14, 2018: Journal of Neurophysiology
https://www.readbyqxmd.com/read/29524627/calcium-activated-sk-potassium-channels-are-key-modulators-of-the-pacemaker-frequency-in-locus-coeruleus-neurons
#10
Lina A Matschke, Susanne Rinné, Terrance P Snutch, Wolfgang H Oertel, Amalia M Dolga, Niels Decher
The physiological, intrinsic activity of noradrenergic locus coeruleus (LC) neurons is important for the control of sleep/wakefulness, cognition and autonomous body functions. Dysregulations of the LC-noradrenergic network contribute to the pathogenesis of psychiatric disorders and are key findings in early stages of neurodegenerative diseases. Therefore, identifying ion channels mediating the intrinsic pacemaking mechanism of LC neurons, which is in turn directly coupled to Ca2+ homeostasis and cell survival signaling pathways, can help to foster our understanding of the vulnerability of these neurons in neurodegenerative diseases...
April 2018: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29515812/cascade-and-parallel-combination-cpc-of-adaptive-filters-for-estimating-heart-rate-during-intensive-physical-exercise-from-photoplethysmographic-signal
#11
Mohammad Tariqul Islam, Sk Tanvir Ahmed, Ishmam Zabir, Celia Shahnaz, Shaikh Anowarul Fattah
Photoplethysmographic (PPG) signal is getting popularity for monitoring heart rate in wearable devices because of simplicity of construction and low cost of the sensor. The task becomes very difficult due to the presence of various motion artefacts. In this study, an algorithm based on cascade and parallel combination (CPC) of adaptive filters is proposed in order to reduce the effect of motion artefacts. First, preliminary noise reduction is performed by averaging two channel PPG signals. Next in order to reduce the effect of motion artefacts, a cascaded filter structure consisting of three cascaded adaptive filter blocks is developed where three-channel accelerometer signals are used as references to motion artefacts...
February 2018: Healthcare Technology Letters
https://www.readbyqxmd.com/read/29511675/regulation-of-spontaneous-contractions-in-intact-rat-bladder-strips-and-the-effects-of-hydrogen-peroxide
#12
Mingshuai Wang, Nianzeng Xing, Liyang Wu, Wen-Chu Huang, Zhenqun Xu, Guiming Liu
Enhanced spontaneous contractions are associated with overactive bladder. Elevated levels of reactive oxygen species might contribute to enhanced spontaneous contractions. We investigated the regulation of spontaneous contractions and the effects of hydrogen peroxide (H2 O2 ) in intact rat bladder strips. The spontaneous contractions were measured using a tissue bath system. The vehicle or the specific activators/blockers were applied and followed by the application of 0.003 g% H2 O2 . The basal tension, amplitude, and frequency of spontaneous contractions were quantified...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29511121/a-role-for-corticotropin-releasing-factor-signaling-in-the-lateral-habenula-and-its-modulation-by-early-life-stress
#13
Michael E Authement, Ludovic D Langlois, Ryan D Shepard, Caroline A Browne, Irwin Lucki, Haifa Kassis, Fereshteh S Nugent
Centrally released corticotropin-releasing factor or hormone (extrahypothalamic CRF or CRH) in the brain is involved in the behavioral and emotional responses to stress. The lateral habenula (LHb) is an epithalamic brain region involved in value-based decision-making and stress evasion. Through its inhibition of dopamine-mediated reward circuitry, the increased activity of the LHb is associated with addiction, depression, schizophrenia, and behavioral disorders. We found that extrahypothalamic CRF neurotransmission increased neuronal excitability in the LHb...
March 6, 2018: Science Signaling
https://www.readbyqxmd.com/read/29496495/assessment-of-the-trpm8-inhibitor-amtb-in-breast-cancer-cells-and-its-identification-as-an-inhibitor-of-voltage-gated-sodium-channels
#14
Kunsala T D S Yapa, Jennifer Deuis, Amelia A Peters, Paraic A Kenny, Sarah J Roberts-Thomson, Irina Vetter, Gregory R Monteith
AIMS: To assess levels of the calcium permeable transient receptor potential cation channel, subfamily melastatin, member 8 (TRPM8) in breast cancer molecular subtypes and to assess the consequences of TRPM8 pharmacological inhibition with AMTB (an inhibitor of TRPM8) on breast cancer cell lines. MATERIALS AND METHODS: Cell viability and migration of breast cancer cells was determined using MTS assays and wound healing assays, respectively. RNA-Seq analysis of breast tumours and qPCR in breast cancer cell lines were used to assess mRNA levels of ion channels...
April 1, 2018: Life Sciences
https://www.readbyqxmd.com/read/29384449/similar-nicotinic-excitability-responses-across-the-developing-hippocampal-formation-are-regulated-by-small-conductance-calcium-activated-potassium-channels
#15
Beryl Y T Chung, Craig D C Bailey
The hippocampal formation forms a cognitive circuit that is critical for learning and memory. Cholinergic input to nicotinic acetylcholine receptors plays an important role in the normal development of principal neurons within the hippocampal formation. However, the ability of nicotinic receptors to stimulate principal neurons across all regions of the developing hippocampal formation has not been determined. We show here that heteromeric nicotinic receptors mediate direct inward current and depolarization responses in principal neurons across the hippocampal formation of the young postnatal mouse...
January 31, 2018: Journal of Neurophysiology
https://www.readbyqxmd.com/read/29305679/decreased-coronary-arteriolar-response-to-k-ca-channel-opener-after-cardioplegic-arrest-in-diabetic-patients
#16
Yuhong Liu, Victoria Cole, Isabella Lawandy, Afshin Ehsan, Frank W Sellke, Jun Feng
We have recently found that diabetes is associated with the inactivation of the calcium-activated potassium channels (KCa ) in endothelial cells, which may contribute to endothelial dysfunction in diabetic patients at baseline. In the current study, we further investigated the effects of diabetes on coronary arteriolar responses to the small (SK) and intermediate (IK) KCa opener NS309 in diabetic and non-diabetic patients and correlated that data with the changes in the SK/IK protein expression/distribution in the setting of cardioplegic ischemia and reperfusion (CP) and cardiopulmonary bypass (CPB)...
January 5, 2018: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29214998/structural-insights-into-the-potency-of-sk-channel-positive-modulators
#17
Young-Woo Nam, Razan Orfali, Tingting Liu, Kunqian Yu, Meng Cui, Heike Wulff, Miao Zhang
Small-conductance Ca2+ -activated K+ (SK) channels play essential roles in the regulation of cellular excitability and have been implicated in neurological and cardiovascular diseases through both animal model studies and human genetic association studies. Over the past two decades, positive modulators of SK channels such as NS309 and 1-EBIO have been developed. Our previous structural studies have identified the binding pocket of 1-EBIO and NS309 that is located at the interface between the channel and calmodulin...
December 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29200999/confirming-a-role-for-%C3%AE-9nachrs-and-sk-potassium-channels-in-type-ii-hair-cells-of-the-turtle-posterior-crista
#18
Xiaorong Xu Parks, Donatella Contini, Paivi M Jordan, Joseph C Holt
In turtle posterior cristae, cholinergic vestibular efferent neurons (VENs) synapse on type II hair cells, bouton afferents innervating type II hair cells, and afferent calyces innervating type I hair cells. Electrical stimulation of VENs releases acetylcholine (ACh) at these synapses to exert diverse effects on afferent background discharge including rapid inhibition of bouton afferents and excitation of calyx-bearing afferents. Efferent-mediated inhibition is most pronounced in bouton afferents innervating type II hair cells near the torus, but becomes progressively smaller and briefer when moving longitudinally through the crista toward afferents innervating the planum...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29136290/the-role-of-ca-2-dependent-k-channels-at-the-rat-corticostriatal-synapses-revealed-by-paired-pulse-stimulation
#19
Angel A Robles Gómez, Ana V Vega, Carolina Gónzalez-Sandoval, Jaime Barral
Potassium channels play an important role in modulating synaptic activity both at presynaptic and postsynaptic levels. We have shown before that presynaptically located KV and KIR channels modulate the strength of corticostriatal synapses in rat brain, but the role of other types of potassium channels at these synapses remains largely unknown. Here, we show that calcium-dependent potassium channels BK-type but not SK-type channels are located presynaptically in corticostriatal synapses. We stimulated cortical neurons in rat brain slices and recorded postsynaptic excitatory potentials (EPSP) in medium spiny neurons (MSN) in dorsal neostriatum...
February 2018: Synapse
https://www.readbyqxmd.com/read/29058675/dendritic-small-conductance-calcium-activated-potassium-channels-activated-by-action-potentials-suppress-epsps-and-gate-spike-timing-dependent-synaptic-plasticity
#20
Scott L Jones, Minh-Son To, Greg J Stuart
Small conductance calcium-activated potassium channels (SK channels) are present in spines and can be activated by backpropagating action potentials (APs). This suggests they may play a critical role in spike-timing dependent synaptic plasticity (STDP). Consistent with this idea, EPSPs in both cortical and hippocampal pyramidal neurons were suppressed by preceding APs in an SK-dependent manner. In cortical pyramidal neurons EPSP suppression by preceding APs depended on their precise timing as well as the distance of activated synapses from the soma, was dendritic in origin, and involved SK-dependent suppression of NMDA receptor activation...
October 23, 2017: ELife
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