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B Bonito, D R P Sauter, A Schwab, M B A Djamgoz, I Novak
In the recent decades, ion channels became the focus of cancer biologists, as many channels are overexpressed in tumour tissue and functionally they are linked to abnormal cell behaviour with processes including apoptosis, chemo- and radioresistance, proliferation and migration. KCa3.1 is a Ca(2+)-activated K(+) channel that plays a central role in tumour progression in many cancer types. Therefore, the aim of the present study was to investigate KCa3.1 expression in pancreatic cancer cells and assess possible implications to disease progression...
October 17, 2016: Pflügers Archiv: European Journal of Physiology
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
Li-Ping Wang, Su-Jing Fan, Shu-Min Li, Xiao-Jun Wang, Jun-Ling Gao, Xiu-Hong Yang
The intermediate-conductance Ca(2+)-activated K(+) (KCa3.1) channel plays a vital role in myocardial fibrosis induced by angiotensin (Ang) II. However, as the antagonists of Ang II, the effect of angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas axis on KCa3.1 channel during myocardial fibrosis remains unknown. This study was designed to explore the function of KCa3.1 channel in the cardioprotective role of ACE2-Ang-(1-7)-Mas. Wild-type (WT) mice, hACE2 transgenic mice (Tg), and ACE2 deficiency mice (ACE2(-/-)) were administrated with Ang II by osmotic mini-pumps...
September 3, 2016: Pflügers Archiv: European Journal of Physiology
Gen Chen, Jun-Jie Wang, Cang-Bao Xu, Lei Cao, Jie Lin, Xu-Ping Qing, Si-Yu Liu, En-Qi Liu, Jie Li
Minimally modified low-density lipoprotein (mmLDL) is a well-known risk factor for cardiovascular diseases. The present study was designed to investigate the role of mmLDL in the endothelium-dependent relaxation of mouse mesenteric arteries. A sensitive myograph system was employed to examine the endothelial function of mesenteric arteries. mRNA and protein expression levels were determined using real-time PCR and Western blotting, respectively. The ultramicrostructure of mesenteric vascular beds was investigated using a transmission electron microscope...
September 1, 2016: Journal of Vascular Research
Mengni Yi, Panpan Yu, Qin Lu, Herbert M Geller, Zhihua Yu, Hongzhuan Chen
Alzheimer's disease (AD) is the most common type of dementia and is characterized by a progression from decline of episodic memory to a global impairment of cognitive function. Astrogliosis is a hallmark feature of AD, and reactive gliosis has been considered as an important target for intervention in various neurological disorders. We previously found in astrocyte cultures that the expression of the intermediate conductance calcium-activated potassium channel KCa3.1 was increased in reactive astrocytes induced by TGF-β, while pharmacological blockade or genetic deletion of KCa3...
October 2016: Molecular and Cellular Neurosciences
Sinoy Sugunan, Sreekala S Nampoothiri, Tanya Garg, Rajanikant G Krishnamurthy
KCa3.1 protein is part of a heterotetrameric voltage-independent potassium channel, the activity of which depends on the intracellular calcium binding to calmodulin. KCa3.1 is immensely significant in regulating immune responses and primarily expressed in cells of hematopoietic lineage. It is one of the attractive pharmacological targets that are known to inhibit neuroinflammation. KCa3.1 blockers mediate neuroprotection through multiple mechanisms, such as by targeting microglia-mediated neuronal killing. KCa3...
August 22, 2016: CNS & Neurological Disorders Drug Targets
Shekhar Srivastava, Saswati Panda, Zhai Li, Stephen R Fuhs, Tony Hunter, Dennis J Thiele, Stevan R Hubbard, Edward Y Skolnik
KCa2.1, KCa2.2, KCa2.3 and KCa3.1 constitute a family of mammalian small- to intermediate-conductance potassium channels that are activated by calcium-calmodulin. KCa3.1 is unique among these four channels in that activation requires, in addition to calcium, phosphorylation of a single histidine residue (His358) in the cytoplasmic region, by nucleoside diphosphate kinase-B (NDPK-B). The mechanism by which KCa3.1 is activated by histidine phosphorylation is unknown. Histidine phosphorylation is well characterized in prokaryotes but poorly understood in eukaryotes...
2016: ELife
Yaobing Chen, Dong Kuang, Xia Zhao, Dong Chen, Xiaoyan Wang, Qin Yang, Jie Wan, Yuanli Zhu, Yu Wang, Shiying Zhang, Ying Wang, Qiang Tang, Mikio Masuzawa, Guoping Wang, Yaqi Duan
Angiosarcoma is a rare malignant mesenchymal tumor with poor prognosis. We aimed to identify malignancy-associated miRNAs and their target genes, and explore biological functions of miRNA and its target in angiosarcoma. By miRNA microarrays and reverse transcription polymerase chain reaction, we identified 1 up-regulated miRNA (miR-222-3p) and 3 down-regulated miRNAs (miR-497-5p, miR-378-3p and miR-483-5p) in human angiosarcomas compared with human capillary hemangiomas. The intermediate-conductance calcium activated potassium channel KCa3...
August 12, 2016: Oncotarget
Ulf Simonsen, Christine Wandall-Frostholm, Aida Oliván-Viguera, Ralf Köhler
It has been suggested that the transient receptor potential cation (TRP) channel subfamily V (vanilloid) type 4 (TRPV4) and intermediate-conductance calcium-activated potassium (KCa3.1) channels contribute to endothelium-dependent vasodilation. Here we summarize very recent evidence for a synergistic interplay of TRPV4 and KCa3.1 channels in lung disease. Among the endothelial Ca(2+) -permeable TRPs, TRPV4 is best characterized and produces arterial dilation by stimulating Ca(2+) -dependent NO synthesis and endothelium-dependent hyperpolarization...
August 6, 2016: Acta Physiologica
Ilya Kovalenko, Andrea Glasauer, Laura Schöckel, Daniel R P Sauter, Alexander Ehrmann, Florian Sohler, Andrea Hägebarth, Ivana Novak, Sven Christian
Pancreatic ductal adenocarcinoma (PDAC) represents the most common form of pancreatic cancer with rising incidence in developing countries and overall 5-year survival rates of less than 5%. The most frequent mutations in PDAC are gain-of-function mutations in KRAS as well as loss-of-function mutations in p53. Both mutations have severe impacts on the metabolism of tumor cells. Many of these metabolic changes are mediated by transporters or channels that regulate the exchange of metabolites and ions between the intracellular compartment and the tumor microenvironment...
2016: PloS One
Nóra Faragó, Ágnes Katalin Kocsis, Csilla Braskó, Sándor Lovas, Márton Rózsa, Judith Baka, Balázs Kovács, Katalin Mikite, Viktor Szemenyei, Gábor Molnár, Attila Ozsvár, Gáspár Oláh, Ildikó Piszár, Ágnes Zvara, Attila Patócs, Pál Barzó, László G Puskás, Gábor Tamás
Functional and molecular changes associated with pathophysiological conditions are relatively easily detected based on tissue samples collected from patients. Population specific cellular responses to disease might remain undiscovered in samples taken from organs formed by a multitude of cell types. This is particularly apparent in the human cerebral cortex composed of a yet undefined number of neuron types with a potentially different involvement in disease processes. We combined cellular electrophysiology, anatomy and single cell digital PCR in human neurons identified in situ for the first time to assess mRNA expression and corresponding functional changes in response to edema and increased intracranial pressure...
2016: Acta Neuropathologica Communications
Saswati Panda, Shekhar Srivastava, Zhai Li, Martin Vaeth, Stephen R Fuhs, Tony Hunter, Edward Y Skolnik
Whereas phosphorylation of serine, threonine, and tyrosine is exceedingly well characterized, the role of histidine phosphorylation in mammalian signaling is largely unexplored. Here we show that phosphoglycerate mutase family 5 (PGAM5) functions as a phosphohistidine phosphatase that specifically associates with and dephosphorylates the catalytic histidine on nucleoside diphosphate kinase B (NDPK-B). By dephosphorylating NDPK-B, PGAM5 negatively regulates CD4(+) T cells by inhibiting NDPK-B-mediated histidine phosphorylation and activation of the K(+) channel KCa3...
August 4, 2016: Molecular Cell
R Köhler, A Oliván-Viguera, H Wulff
Endothelial calcium/calmodulin-gated K channels of small (KCa2.3) and intermediate conductance (KCa3.1) produce membrane hyperpolarization and endothelium-dependent hyperpolarization (EDH)-mediated vasodilation. Dysfunctions of the two channels and ensuing EDH impairments are found in several cardiovascular pathologies such as diabetes, atherosclerosis, postangioplastic neointima formation, but also inflammatory disease, cancer, and organ fibrosis. Moreover, KCa3.1 plays an important role in endothelial barrier dysfunction, edema formation in cardiac and pulmonary disease, and in ischemic stroke...
2016: Advances in Pharmacology
Linda Sevelsted Møller, Annette Dam Fialla, Robert Schierwagen, Matteo Biagini, Christian Liedtke, Wim Laleman, Sabine Klein, Winfried Reul, Lars Koch Hansen, Maj Rabjerg, Vikrant Singh, Joaquin Surra, Jesus Osada, Roland Reinehr, Ove B Schaffalitzky de Muckadell, Ralf Köhler, Jonel Trebicka
The calcium-activated potassium channel KCa3.1 controls different cellular processes such as proliferation and volume homeostasis. We investigated the role of KCa3.1 in experimental and human liver fibrosis. KCa3.1 gene expression was investigated in healthy and injured human and rodent liver. Effect of genetic depletion and pharmacological inhibition of KCa3.1 was evaluated in mice during carbon tetrachloride induced hepatic fibrogenesis. Transcription, protein expression and localisation of KCa3.1 was analysed by reverse transcription polymerase chain reaction, Western blot and immunohistochemistry...
2016: Scientific Reports
S L Zhang, J S Xu, S Yang, Y L Bai, J X Zhang, L W Cui, Q Y Yu
OBJECTIVE: To observe the role of TRAM-34 (1-((2-chlorophenyl)diphenylmethyl)-1H-pyrazole), the blocker of intermediate conductance calcium-activated potassium channel (KCa3.1), on β-glycerophosphate induced vascular calcification in vitro. METHODS: Vascular smooth muscle cells(VSMCs) were obtained from rat thoracic aorta, and VSMCs after the fourth passage and aortic rings were divided into control group (cultured in DMEM with 10% fetal bovine serum), high phosphorus group (cultured in DMEM with 10% fetal bovine serum and 10% β-glycerophosphate) and TRAM-34 group(20 nmol/L TRAM-34 was added into high phosphorus DMEM)...
June 24, 2016: Zhonghua Xin Xue Guan Bing za Zhi
Malika Faouzi, Frederic Hague, Dirk Geerts, Anne-Sophie Ay, Marie Potier-Cartereau, Ahmed Ahidouch, Halima Ouadid-Ahidouch
Intracellular Ca2+ levels are important regulators of cell cycle and proliferation. We, and others, have previously reported the role of KCa3.1 (KCNN4) channels in regulating the membrane potential and the Ca2+ entry in association with cell proliferation. However, the relevance of KC3.1 channels in cancer prognosis as well as the molecular mechanism of Ca2+ entry triggered by their activation remain undetermined. Here, we show that RNAi-mediated knockdown of KCa3.1 and/or TRPC1 leads to a significant decrease in cell proliferation due to cell cycle arrest in the G1 phase...
May 10, 2016: Oncotarget
Nicole Glaser, Christopher Little, Weei Lo, Michael Cohen, Daniel Tancredi, Heike Wulff, Martha O'Donnell
BACKGROUND: Diabetic ketoacidosis (DKA) causes brain injuries in children ranging from subtle to life-threatening. Previous studies suggest that DKA-related brain injury may involve both stimulation of Na-K-Cl cotransport and microglial activation. Other studies implicate the Na-K-Cl cotransporter and the Ca-activated K channel KCa3.1 in activation of microglia and ischemia-induced brain edema. In this study, we determined whether inhibiting cerebral Na-K-Cl cotransport or KCa3.1 could reduce microglial activation and decrease DKA-related inflammatory changes in the brain...
May 13, 2016: Pediatric Diabetes
Mengni Yi, Fangfang Dou, Qin Lu, Zhihua Yu, Hongzhuan Chen
Reactive astrogliosis is widely considered to contribute to pathogenic responses to stress and brain injury and to diseases as diverse as ischemia and neurodegeneration. We previously found that expression of the intermediate-conductance calcium-activated potassium channel (KCa3.1) involved in TGF-β-activated astrogliosis. In the present study, we investigated whether migration of cortical astrocytes following mechanical scratch injury involves the KCa3.1 channel, which contributes to Ca(2+)-mediated migration in other cells...
June 15, 2016: Neuroscience Letters
Poh-Shiow Yeh, Shyh-Jong Wu, Te-Yu Hung, Yan-Ming Huang, Chia-Wei Hsu, Chun-I Sze, Yi-Jung Hsieh, Chin-Wei Huang, Sheng-Nan Wu
BACKGROUND: Temozolomide (TMZ), an oral alkylator of the imidazotetrazine family, is used to treat glioma. Whether this drug has any ionic effects in glioma cells remains largely unclear. METHODS: With the aid of patch-clamp technology, we investigated the effects of TMZ on the ionic currents in U373 glioma cells. The mRNA expression of KCNN4 (KCa3.1) in U373 glioma cells and TMZ's effect on K+ currents in these KCNN4 siRNA-transfected U373 cells were investigated...
2016: Cellular Physiology and Biochemistry
Fang Ye, Youtian Hu, Weiwei Yu, Zili Xie, Jun Hu, Zhijian Cao, Wenxin Li, Yingliang Wu
The Kv1.3 channel-acting scorpion toxins usually adopt the conserved anti-parallel β-sheet domain as the binding interface, but it remains challenging to discover some highly selective Kv1.3 channel-acting toxins. In this work, we investigated the pharmacological profile of the Kv1.3 channel-acting BmKTX-D33H, a structural analogue of the BmKTX scorpion toxin. Interestingly, BmKTX-D33H, with its conserved anti-parallel β-sheet domain as a Kv1.3 channel-interacting interface, exhibited more than 1000-fold selectivity towards the Kv1...
April 2016: Toxins
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