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https://www.readbyqxmd.com/read/27872049/contribution-of-kv1-5-channel-to-h2o2-induced-human-arteriolar-dilation-and-its-modulation-by-coronary-artery-disease
#1
Yoshinori Nishijima, Sheng Cao, Dawid S Chabowski, Ankush Korishettar, Alyce Ge, Xiaodong Zheng, Rodney Sparapani, David D Gutterman, David X Zhang
RATIONALE: Hydrogen peroxide (H2O2) regulates vascular tone in the human microcirculation under physiological and pathophysiological conditions. It dilates arterioles by activating BKCa channels in subjects with coronary artery disease (CAD), but its mechanisms of action in subjects without CAD (non-CAD) as compared to those with CAD remain unknown. OBJECTIVE: We hypothesize that H2O2-elicited dilation involves different K(+) channels in non-CAD versus CAD, resulting in an altered capacity for vasodilation during disease...
November 21, 2016: Circulation Research
https://www.readbyqxmd.com/read/27861889/margatoxin-bound-quantum-dots-as-a-novel-inhibitor-of-the-voltage-gated-ion-channel-kv1-3
#2
Austin B Schwartz, Anshika Kapur, Wentao Wang, Zhenbo Huang, Erminia Fardone, Goutam Palui, Hedi Mattoussi, Debra Ann Fadool
Venom-derived ion channel inhibitors have strong channel selectivity, potency, and stability; however, tracking delivery to their target can be challenging. Herein, we utilized luminescent quantum dots (QDs) conjugated to margatoxin (MgTx) as a traceable vehicle to target a voltage-dependent potassium channel, Kv1.3, which has a select distribution and well characterized role in immunity, glucose metabolism, and sensory ability. We screened both unconjugated (MgTx) and conjugated MgTx (QD-MgTx) for their ability to inhibit Shaker channels Kv1...
November 8, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27816768/human-immunodeficiency-virus-protein-tat-induces-oligodendrocyte-injury-by-enhancing-outward-k-current-conducted-by-kv1-3
#3
Han Liu, Jianuo Liu, Enquan Xu, Guihua Tu, Minglei Guo, Shangdong Liang, Huangui Xiong
Brain white matter damage is frequently detected in patients infected with human immunodeficiency virus type 1 (HIV-1). White matter is composed of neuronal axons sheathed by oligodendrocytes (Ols), the myelin-forming cells in central nervous system. Ols are susceptible to HIV-1 viral trans-activator of transcription (Tat) and injury of Ols results in myelin sheath damage. It has been demonstrated that activation of voltage-gated K(+) (KV) channels induces cell apoptosis and Ols predominantly express K(+) channel KV1...
November 2, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27815390/kv1-3-channels-mark-functionally-competent-cd8-tumor-infiltrating-lymphocytes-in-head-and-neck-cancer
#4
Ameet A Chimote, Peter Hajdu, Alexandros M Sfyris, Brittany N Gleich, Trisha Wise-Draper, Keith A Casper, Laura Conforti
Tumor infiltrating lymphocytes (TIL) are potent mediators of an anti-tumor response. However, their function is attenuated in solid tumors. CD8(+) T cell effector functions such as cytokine and granzyme production depend on cytoplasmic Ca(2+), which is controlled by ion channels. In particular, Kv1.3 channels regulate the membrane potential and Ca(2+) influx in human effector memory T (TEM) cells. In this study, we assessed the contribution of reduced Kv1.3 and Ca(2+) flux on TIL effector function in head and neck cancer (HNC)...
November 4, 2016: Cancer Research
https://www.readbyqxmd.com/read/27802162/the-c-terminal-domain-of-kv1-3-regulates-functional-interactions-with-the-kcne4-subunit
#5
Laura Solé, Sara R Roig, Albert Vallejo-Gracia, Antonio Serrano-Albarrás, Ramón Martínez-Mármol, Michael M Tamkun, Antonio Felipe
The voltage-dependent K(+) channel Kv1.3 (also known as KCNA3), which plays crucial roles in leukocytes, physically interacts with KCNE4. This interaction inhibits the K(+) currents because the channel is retained within intracellular compartments. Thus, KCNE subunits are regulators of K(+) channels in the immune system. Although the canonical interactions of KCNE subunits with Kv7 channels are under intensive investigation, the molecular determinants governing the important Kv1.3- KCNE4 association in the immune system are unknown...
November 15, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27796577/regulation-of-human-cardiac-kv1-5-channels-by-extracellular-acidification
#6
Shuang Wang, Wei-Guang Ding, Jia-Yu Bai, Futoshi Toyoda, Min-Jie Wei, Hiroshi Matsuura
Human Kv1.5 channels (hKv1.5) conduct the ultra-rapid delayed rectifier potassium current (I Kur), which plays an important role in action potential repolarization of atrial myocytes. The present study was undertaken to examine the effects of acidic pH on hKv1.5 wild-type (WT) and its pore mutant channels heterologously expressed in Chinese hamster ovary (CHO) cells using site-directed mutagenesis combined with whole-cell patch-clamp technique. Both extracellular and intracellular acidifications equally and reversely reduced the amplitude of hKv1...
October 28, 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/27789942/comparison-of-cellular-effects-of-starch-coated-spions-and-poly-lactic-co-glycolic-acid-matrix-nanoparticles-on-human-monocytes
#7
Dominik Gonnissen, Ying Qu, Klaus Langer, Cengiz Öztürk, Yuliang Zhao, Chunying Chen, Guiscard Seebohm, Martina Düfer, Harald Fuchs, Hans-Joachim Galla, Kristina Riehemann
Within the last years, progress has been made in the knowledge of the properties of medically used nanoparticles and their toxic effects, but still, little is known about their influence on cellular processes of immune cells. The aim of our comparative study was to present the influence of two different nanoparticle types on subcellular processes of primary monocytes and the leukemic monocyte cell line MM6. We used core-shell starch-coated superparamagnetic iron oxide nanoparticles (SPIONs) and matrix poly(lactic-co-glycolic acid) (PLGA) nanoparticles for our experiments...
2016: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/27765883/inhibitory-effects-of-telmisartan-on-culture-and-proliferation-of-and-kv1-3-potassium-channel-expression-in-peripheral-blood-cd4-t-lymphocytes-from-xinjiang-kazakh-patients-with-hypertension
#8
Sha-Sha Huang, Qiu-Bing Zhang, Qing-Yan Yuan, Si-Li He, Yuan-Ming Zhang
INTRODUCTION: Activation of T lymphocytes, for which potassium channels are essential, is involved in the development of hypertension. In this study, we explored the inhibitory effects of telmisartan on the culture and proliferation of and Kv1.3 potassium channel expression in peripheral blood CD4(+) T lymphocytes derived from Xinjiang Kazakh patients with hypertension. METHODS: CD4(+) T-cell samples from hypertensive Kazakh patients and healthy Kazakh people were divided into healthy control, case control, telmisartan, and 4-aminopytidine groups...
October 2016: Journal of the Renin-angiotensin-aldosterone System: JRAAS
https://www.readbyqxmd.com/read/27742566/atrial-fibrillation-therapeutic-potential-of-atrial-k-channel-blockers
#9
Ursula Ravens, Katja E Odening
Despite the epidemiological scale of atrial fibrillation, current treatment strategies are of limited efficacy and safety. Ideally, novel drugs should specifically correct the pathophysiological mechanisms responsible for atrial fibrillation with no other cardiac or extracardiac actions. Atrial-selective drugs are directed toward cellular targets with sufficiently different characteristics in atria and ventricles to modify only atrial function. Several potassium (K(+)) channels with either predominant expression in atria or distinct electrophysiological properties in atria and ventricles can serve as atrial-selective drug targets...
October 12, 2016: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/27696527/differential-kv1-3-kca3-1-and-kir2-1-expression-in-classically-and-alternatively-activated-microglia
#10
Hai M Nguyen, Eva M Grössinger, Makoto Horiuchi, Kyle W Davis, Lee-Way Jin, Izumi Maezawa, Heike Wulff
Microglia are highly plastic cells that can assume different phenotypes in response to microenvironmental signals. Lipopolysaccharide (LPS) and interferon-γ (IFN-γ) promote differentiation into classically activated M1-like microglia, which produce high levels of pro-inflammatory cytokines and nitric oxide and are thought to contribute to neurological damage in ischemic stroke and Alzheimer's disease. IL-4 in contrast induces a phenotype associated with anti-inflammatory effects and tissue repair. We here investigated whether these microglia subsets vary in their K(+) channel expression by differentiating neonatal mouse microglia into M(LPS) and M(IL-4) microglia and studying their K(+) channel expression by whole-cell patch-clamp, quantitative PCR and immunohistochemistry...
January 2017: Glia
https://www.readbyqxmd.com/read/27663736/rational-design-of-a-kv1-3-channel-blocking-antibody-as-a-selective-immunosuppressant
#11
Rongsheng E Wang, Ying Wang, Yuhan Zhang, Chase Gabrelow, Yong Zhang, Victor Chi, Qiangwei Fu, Xiaozhou Luo, Danling Wang, Sean Joseph, Kristen Johnson, Arnab K Chatterjee, Timothy M Wright, Vân T B Nguyen-Tran, John Teijaro, Argyrios N Theofilopoulos, Peter G Schultz, Feng Wang
A variable region fusion strategy was used to generate an immunosuppressive antibody based on a novel "stalk-knob" structural motif in the ultralong complementary-determining region (CDR) of a bovine antibody. The potent Kv1.3 channel inhibitory peptides Moka1-toxin and Vm24-toxin were grafted into different CDRs of the humanized antibodies BVK and Synagis (Syn) using both β-sheet and coiled-coil linkers. Structure-activity relationship efforts led to generation of the fusion protein Syn-Vm24-CDR3L, which demonstrated excellent selectivity and potency against effector human memory T cells (subnanomolar to picomolar EC50 values)...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27660193/role-of-individual-disulfide-bridges-in-the-conformation-and-activity-of-spinoxin-%C3%AE-ktx6-13-a-potassium-channel-toxin-from-heterometrus-spinifer-scorpion-venom
#12
Yoko Yamaguchi, Steve Peigneur, Junyi Liu, Shiho Uemura, Takeru Nose, Selvanayagam Nirthanan, Ponnampalam Gopalakrishnakone, Jan Tytgat, Kazuki Sato
Spinoxin (SPX; α-KTx6.13), isolated from venom of the scorpion Heterometrus spinifer, is a K(+) channel-specific peptide toxin (KTx), which adopts a cysteine-stabilized α/β scaffold that is cross-linked by four disulfide bridges (Cys1-Cys5, Cys2-Cys6, Cys3-Cys7, and Cys4-Cys8). To investigate the role of the individual disulfide bonds in the structure-activity relationship of SPX, we synthesized four SPX analogs in which each pair of cysteine residues was replaced by alanine residues. The analysis of circular dichroism spectra and inhibitory activity against Kv1...
September 19, 2016: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/27638047/comparison-of-voltage-gated-k-currents-in-arterial-myocytes-with-heterologously-expressed-k-v-subunits
#13
Robert H Cox, Samantha Fromme
We have shown that three components contribute to functional voltage gated K(+) (K v) currents in rat small mesenteric artery myocytes: (1) Kv1.2 plus Kv1.5 with Kvβ1.2 subunits, (2) Kv2.1 probably associated with Kv9.3 subunits, and (3) Kv7.4 subunits. To confirm and address subunit stoichiometry of the first two, we have compared the biophysical properties of K v currents in small mesenteric artery myocytes with those of Kv subunits heterologously expressed in HEK293 cells using whole cell voltage clamp methods...
September 16, 2016: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/27626381/ionic-immune-suppression-within-the-tumour-microenvironment-limits-t-cell-effector-function
#14
Robert Eil, Suman K Vodnala, David Clever, Christopher A Klebanoff, Madhusudhanan Sukumar, Jenny H Pan, Douglas C Palmer, Alena Gros, Tori N Yamamoto, Shashank J Patel, Geoffrey C Guittard, Zhiya Yu, Valentina Carbonaro, Klaus Okkenhaug, David S Schrump, W Marston Linehan, Rahul Roychoudhuri, Nicholas P Restifo
Tumours progress despite being infiltrated by tumour-specific effector T cells. Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers. Here, we show that necrosis releases intracellular potassium ions into the extracellular fluid of mouse and human tumours, causing profound suppression of T cell effector function. Elevation of the extracellular potassium concentration ([K(+)]e) impairs T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes...
September 14, 2016: Nature
https://www.readbyqxmd.com/read/27573545/the-antifungal-plant-defensin-atpdf2-3-from-arabidopsis-thaliana-blocks-potassium-channels
#15
Kim Vriens, Steve Peigneur, Barbara De Coninck, Jan Tytgat, Bruno P A Cammue, Karin Thevissen
Scorpion toxins that block potassium channels and antimicrobial plant defensins share a common structural CSαβ-motif. These toxins contain a toxin signature (K-C4-X-N) in their amino acid sequence, and based on in silico analysis of 18 plant defensin sequences, we noted the presence of a toxin signature (K-C5-R-G) in the amino acid sequence of the Arabidopsis thaliana defensin AtPDF2.3. We found that recombinant (r)AtPDF2.3 blocks Kv1.2 and Kv1.6 potassium channels, akin to the interaction between scorpion toxins and potassium channels...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27571906/blockade-of-the-kv1-3-k-channel-enhances-bcg-vaccine-efficacy-by-expanding-central-memory-t-lymphocytes
#16
Dhiraj Kumar Singh, Ved Prakash Dwivedi, Anand Ranganathan, William R Bishai, Luc Van Kaer, Gobardhan Das
Tuberculosis (TB) is the oldest known infectious disease, yet there is no effective vaccine against adult pulmonary TB. Emerging evidence indicates that T helper (Th)1 and Th17 cells play important roles in host protection against TB. However, TB vaccine efficacy in mice is critically dependent on the balance between antigen-specific central memory T (Tcm) to effector memory T (Tem) cells. Specifically, a high Tcm to Tem cell ratio is essential for optimal vaccine efficacy. Here, we show that pharmacological inhibition of Kv1...
August 28, 2016: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/27568555/decrease-of-a-current-mediated-by-kv1-3-channels-causes-striatal-cholinergic-interneuron-hyperexcitability-in-experimental-parkinsonism
#17
Cecilia Tubert, Irene R E Taravini, Eden Flores-Barrera, Gonzalo M Sánchez, María Alejandra Prost, María Elena Avale, Kuei Y Tseng, Lorena Rela, Mario Gustavo Murer
The mechanism underlying a hypercholinergic state in Parkinson's disease (PD) remains uncertain. Here, we show that disruption of the Kv1 channel-mediated function causes hyperexcitability of striatal cholinergic interneurons in a mouse model of PD. Specifically, our data reveal that Kv1 channels containing Kv1.3 subunits contribute significantly to the orphan potassium current known as IsAHP in striatal cholinergic interneurons. Typically, this Kv1 current provides negative feedback to depolarization that limits burst firing and slows the tonic activity of cholinergic interneurons...
September 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27542263/tumor-reducing-effect-of-the-clinically-used-drug-clofazimine-in-a-scid-mouse-model-of-pancreatic-ductal-adenocarcinoma
#18
Angela Zaccagnino, Antonella Managò, Luigi Leanza, Artur Gontarewitz, Bernhard Linder, Michele Azzolini, Lucia Biasutto, Mario Zoratti, Roberta Peruzzo, Karen Legler, Anna Trauzold, Holger Kalthoff, Ildiko Szabo
Pancreatic ductal adenocarcinoma (PDAC) represents the most common form of pancreatic cancer with rising incidence in developing countries. Unfortunately, the overall 5-year survival rate is still less than 5%. The most frequent oncogenic mutations in PDAC are loss-of function mutations in p53 and gain-of-function mutations in KRAS. Here we show that clofazimine (Lamprene), a drug already used in the clinic for autoimmune diseases and leprosy, is able to efficiently kill in vitro five different PDAC cell lines harboring p53 mutations...
August 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27540364/the-role-of-dpo-1-and-xe991-sensitive-potassium-channels-in-perivascular-adipose-tissue-mediated-regulation-of-vascular-tone
#19
Dmitry Tsvetkov, Jean-Yves Tano, Mario Kassmann, Ning Wang, Rudolf Schubert, Maik Gollasch
The anti-contractile effect of perivascular adipose tissue (PVAT) is an important mechanism in the modulation of vascular tone in peripheral arteries. Recent evidence has implicated the XE991-sensitive voltage-gated KV (KCNQ) channels in the regulation of arterial tone by PVAT. However, until now the in vivo pharmacology of the involved vascular KV channels with regard to XE991 remains undetermined, since XE991 effects may involve Ca(2+) activated BKCa channels and/or voltage-dependent KV1.5 channels sensitive to diphenyl phosphine oxide-1 (DPO-1)...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27511450/clinical-pathologic-correlations-in-vgkc-subtyped-autoimmune-painful-polyneuropathy
#20
Rajat Lahoria, Sean J Pittock, Avi Gadoth, JaNean K Engelstad, Vanda A Lennon, Christopher J Klein
INTRODUCTION: Voltage-gated Kv1 potassium channel-complex (VGKC) autoantibodies subtyped for leucine-rich-glioma-inactivated-1 (LGI1), contactin-associated-protein-like-2 (CASPR2), and Kv-IgGs have a spectrum of neurological presentations. Painful polyneuropathy is seen in some patients, but nerve pathology descriptions are lacking. METHODS: Clinicopathologic features were studied in subtyped VGKC-autoantibody seropositive patients who had undergone nerve biopsies...
August 11, 2016: Muscle & Nerve
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