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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
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
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...
October 3, 2016: Glia
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
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
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
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
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
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
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
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
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
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
Adam G Goodwill, Jillian N Noblet, Daniel Sassoon, Lijuan Fu, Ghassan S Kassab, Luke Schepers, B Paul Herring, Trey S Rottgen, Johnathan D Tune, Gregory M Dick
Ion channels in smooth muscle control coronary vascular tone, but the identity of the potassium channels involved requires further investigation. The purpose of this study was to evaluate the functional role of KV1 channels on porcine coronary blood flow using the selective antagonist correolide. KV1 channel gene transcripts were found in porcine coronary arteries, with KCNA5 (encoding KV1.5) being most abundant (P < 0.001). Immunohistochemical staining demonstrated KV1.5 protein in the vascular smooth muscle layer of both porcine and human coronary arteries, including microvessels...
September 2016: Basic Research in Cardiology
Theresa Lowinus, Tanima Bose, Stefan Busse, Mandy Busse, Dirk Reinhold, Burkhart Schraven, Ursula H H Bommhardt
Memantine is approved for the treatment of advanced Alzheimer´s disease (AD) and reduces glutamate-mediated neuronal excitotoxicity by antagonism of N-methyl-D-aspartate receptors. In the pathophysiology of AD immune responses deviate and infectious side effects are observed during memantine therapy. However, the particular effects of memantine on human T lymphocytes are unresolved. Here, we provide evidence that memantine blocks Kv1.3 potassium channels, inhibits CD3-antibody- and alloantigen-induced proliferation and suppresses chemokine-induced migration of peripheral blood T cells of healthy donors...
July 22, 2016: Oncotarget
Jung-Ah Kang, Sang-Heon Park, Sang Phil Jeong, Min-Hee Han, Cho-Rong Lee, Kwang Min Lee, Namhee Kim, Mi-Ryoung Song, Murim Choi, Michael Ye, Guhung Jung, Won-Woo Lee, Soo Hyun Eom, Chul-Seung Park, Sung-Gyoo Park
The role of cereblon (CRBN) in T cells is not well understood. We generated mice with a deletion in Crbn and found cereblon to be an important antagonist of T-cell activation. In mice lacking CRBN, CD4(+) T cells show increased activation and IL-2 production on T-cell receptor stimulation, ultimately resulting in increased potassium flux and calcium-mediated signaling. CRBN restricts T-cell activation via epigenetic modification of Kcna3, which encodes the Kv1.3 potassium channel required for robust calcium influx in T cells...
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
B Wu, B F Wu, Y J Feng, J Tao, Y H Ji
The potassium channel Kv 1.3 plays a vital part in the activation of T lymphocytes and is an attractive pharmacological target for autoimmune diseases. BmP02, a 28-residue peptide isolated from Chinese scorpion (Buthus martensi Karsch) venom, is a potent and selective Kv1.3 channel blocker. However, the mechanism through which BmP02 recognizes and inhibits the Kv1.3 channel is still unclear. In the present study, a complex molecular model of Kv1.3-BmP02 was developed by docking analysis and molecular dynamics simulations...
2016: Scientific Reports
David Meneses, Ana V Vega, Francisco Miguel Torres-Cruz, Jaime Barral
In the last years it has been increasingly clear that KV-channel activity modulates neurotransmitter release. The subcellular localization and composition of potassium channels are crucial to understanding its influence on neurotransmitter release. To investigate the role of KV in corticostriatal synapses modulation, we combined extracellular recording of population-spike and pharmacological blockage with specific and nonspecific blockers to identify several families of KV channels. We induced paired-pulse facilitation (PPF) and studied the changes in paired-pulse ratio (PPR) before and after the addition of specific KV blockers to determine whether particular KV subtypes were located pre- or postsynaptically...
2016: Neural Plasticity
Nóra Legány, Gergely Toldi, Csaba Orbán, Nóra Megyes, Anna Bajnok, Attila Balog
OBJECTIVE: The transient increase of the cytoplasmic free calcium level plays a key role in the process of lymphocyte activation. Kv1.3 and IKCa1 potassium channels are important regulators of the maintenance of calcium influx and present a possible target for selective immunomodulation. DESIGN: Case-control study. SUBJECTS AND METHODS: We took peripheral blood samples from 8 healthy individuals and 15 primary Sjögren's syndrome (pSS) patients...
November 2016: Immunobiology
Stephen L Archer
There is no cure for non-small-cell lung cancer (NSCLC) or pulmonary arterial hypertension (PAH). Therapies lack efficacy and/or are toxic, reflecting a failure to target disease abnormalities that are distinct from processes vital to normal cells. NSCLC and PAH share reversible mitochondrial-metabolic abnormalities which may offer selective therapeutic targets. The following mutually reinforcing, mitochondrial abnormalities favor proliferation, impair apoptosis, and are relatively restricted to PAH and cancer cells: (1) Epigenetic silencing of superoxide dismutase-2 (SOD2) by methylation of CpG islands creates a pseudohypoxic redox environment that causes normoxic activation of hypoxia inducible factor (HIF-1α)...
2016: Advances in Experimental Medicine and Biology
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