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https://www.readbyqxmd.com/read/29329909/the-signaling-role-for-chloride-in-the-bidirectional-communication-between-neurons-and-astrocytes
#1
REVIEW
Corinne S Wilson, Alexander A Mongin
It is well known that the electrical signaling in neuronal networks is modulated by chloride (Cl-) fluxes via the inhibitory GABAA and glycine receptors. Here, we discuss the putative contribution of Cl- fluxes and intracellular Cl- to other forms of information transfer in the CNS, namely the bidirectional communication between neurons and astrocytes. The manuscript (i) summarizes the generic functions of Cl- in cellular physiology, (ii) recaps molecular identities and properties of Cl- transporters and channels in neurons and astrocytes, and (iii) analyzes emerging studies implicating Cl- in the modulation of neuroglial communication...
January 9, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29326302/role-of-clc-k-and-barttin-in-low-potassium-induced-sodium-chloride-cotransporter-activation-and-hypertension-in-mouse-kidney
#2
Naohiro Nomura, Wakana Shoda, Yuanlong Wang, Shintaro Mandai, Taisuke Furusho, Daiei Takahashi, Moko Zeniya, Eisei Sohara, Tatemitsu Rai, Shinichi Uchida
The sodium-chloride cotransporter (NCC) has been identified as a key molecule regulating potassium balance. The mechanisms of NCC regulation during low extracellular potassium concentrations have been studied in vitro. These studies have shown that hyperpolarization increased chloride efflux, leading to the activation of chloride-sensitive WNK kinases and their downstream molecules, including STE20/SPS1-related proline/alanine-rich kinase (SPAK) and NCC. However, this mechanism was not studied in vivo Previously, we developed the barttin hypomorphic mouse ( Bsndneo/neo mice), expressing very low levels of barttin and ClC-K channels, because barttin is an essential ß-subunit of ClC-K...
January 11, 2018: Bioscience Reports
https://www.readbyqxmd.com/read/29287086/dose-duration-reciprocity-for-g-protein-activation-modulation-of-kinase-to-substrate-ratio-alters-cell-signaling
#3
Kang-Ling Liao, Charles E Melvin, Rosangela Sozzani, Roger D Jones, Timothy C Elston, Alan M Jones
In animal cells, activation of heterotrimeric G protein signaling generally occurs when the system's cognate signal exceeds a threshold, whereas in plant cells, both the amount and the exposure time of at least one signal, D-glucose, are used toward activation. This unusual signaling property called Dose-Duration Reciprocity, first elucidated in the genetic model Arabidopsis thaliana, is achieved by a complex that is comprised of a 7-transmembrane REGULATOR OF G SIGNALING (RGS) protein (AtRGS1), a Gα subunit that binds and hydrolyzes nucleotide, a Gβγ dimer, and three WITH NO LYSINE (WNK) kinases...
2017: PloS One
https://www.readbyqxmd.com/read/29237822/potassium-regulated-distal-tubule-wnk-bodies-are-kidney-specific-wnk1-dependent
#4
Cary R Boyd-Shiwarski, Daniel J Shiwarski, Ankita Roy, Lubika J Nkashama, Hima N Namboodiri, Jian Xie, Kara L McClain, Allison Marciszyn, Thomas R Kleyman, Roderick J Tan, Donna B Stolz, Manojkumar A Puthenveedu, Chou-Long Huang, Arohan R Subramanya
With-No-Lysine (WNK) kinases coordinate volume and potassium homeostasis by regulating renal tubular electrolyte transport. In the distal convoluted tubule (DCT), potassium imbalance causes WNK signaling complexes to concentrate into large discrete foci, which we call "WNK bodies." Though these structures have been reported previously, the mechanisms that drive their assembly remain obscure. Here, we show that kidney-specific WNK1 (KS-WNK1), a truncated kinase-defective WNK1 isoform that is highly expressed in the DCT, is critical for WNK body formation...
December 13, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29207108/integrated-analysis-of-gene-expression-and-copy-number-variations-in-met-proto%C3%A2-oncogene%C3%A2-transformed-human-primary-osteoblasts
#5
Ru-Jiang Jia, Chun-Gen Lan, Xiu-Chao Wang, Chun-Tao Gao
The aim of the present study was to screen the potential osteosarcoma (OS)‑associated genes and to obtain additional insight into the pathogenesis of OS. Transcriptional profile (ID: GSE28256) and copy number variations (CNV) profile were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) between MET proto‑oncogene‑transformed human primary osteoblast (MET‑HOB) samples and the control samples were identified using the Linear Models for Microarray Data package. Subsequently, CNV areas and CNVs were identified using cut‑off criterion of >30%‑overlap within the cases using detect_cnv...
November 22, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29134279/dietary-k-and-cl-independently-regulate-basolateral-conductance-in-principal-and-intercalated-cells-of-the-collecting-duct
#6
Viktor N Tomilin, Oleg Zaika, Arohan R Subramanya, Oleh Pochynyuk
The renal collecting duct contains two distinct cell types, principal and intercalated cells, expressing potassium Kir4.1/5.1 (KCNJ10/16) and chloride ClC-K2 (ClC-Kb in humans) channels on their basolateral membrane, respectively. Both channels are thought to play important roles in controlling systemic water-electrolyte balance and blood pressure. However, little is known about mechanisms regulating activity of Kir4.1/5.1 and ClC-K2/b. Here, we employed patch clamp analysis at the single channel and whole cell levels in freshly isolated mouse collecting ducts to investigate regulation of Kir4...
November 13, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/29092909/n-ethylmaleimide-increases-kcc2-activity-by-modulating-transporter-phosphorylation
#7
Leslie C Conway, Ross A Cardarelli, Yvonne E Moore, Karen Jones, Lisa J McWilliams, David J Baker, Matthew P Burnham, Roland W Bürli, Qi Wang, Nicholas J Brandon, Stephen J Moss, Tarek Z Deeb
The K+/Cl- co-transporter (KCC2) is selectively expressed in the adult nervous system, and allows neurons to maintain low intracellular Cl- levels. Thus, KCC2 activity is an essential prerequisite for fast hyperpolarizing synaptic inhibition mediated by type A γ-aminobutyric acid receptors (GABAA), which are Cl- permeable, ligand-gated ion channels. Consistent with this, deficits in the activity of KCC2 lead to epilepsy, and are also implicated in neurodevelopmental disorders, neuropathic pain, and schizophrenia...
November 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29025069/wnk-lysine-deficient-protein-kinase-1-regulates-human-endometrial-stromal-cell-decidualization-proliferation-and-migration-in-part-through-mitogen-activated-protein-kinase-7
#8
Nyssa R Adams, Yasmin M Vasquez, Qianxing Mo, William Gibbons, Ertug Kovanci, Francesco J DeMayo
The differentiation of endometrial stromal cells into decidual cells, termed decidualization, is an integral step in the establishment of pregnancy. The mitogen-activated protein kinase homolog, WNK lysine deficient protein kinase 1 (WNK1), is activated downstream of epidermal growth factor receptor during decidualization. Primary human endometrial stromal cells (HESCs) were subjected to small interfering RNA knockdown of WNK1 followed by in vitro decidualization. This abrogated expression of the decidual marker genes, insulin like growth factor binding protein 1 (IGFBP1) and prolactin (PRL), and prevented adoption of decidual cell morphology...
September 1, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28890722/predicted-functional-implications-of-phosphorylation-of-regulator-of-g-protein-signaling-protein-in-plants
#9
Meral Tunc-Ozdemir, Bo Li, Dinesh K Jaiswal, Daisuke Urano, Alan M Jones, Matthew P Torres
Heterotrimeric G proteins function in development, biotic, and abiotic stress responses, hormone signaling as well as sugar sensing. We previously proposed that discrimination of these various external signals in the G protein pathway is accomplished in plants by membrane-localized receptor-like kinases (RLKs) rather than G-protein-coupled receptors. Arabidopsis thaliana Regulator of G Signaling protein 1 (AtRGS1) modulates G protein activation and is phosphorylated by several RLKs and by WITH-NO-LYSINE kinases (WNKs)...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28881465/wnk-signaling-inhibitors-as-potential-antihypertensive-drugs
#10
REVIEW
Mubarak A AlAmri, Hachemi Kadri, Binar A Dhiani, Shumail Mahmood, Abdulrahman Elzwawi, Youcef Mehellou
Since the discovery of WNK mutations that cause an inherited form of hypertension in humans, there has been increasing interest in targeting WNK signaling as a novel strategy for modulating blood pressure. This notion is now supported by numerous mouse models with impaired WNK signaling that exhibit reduced blood pressure. Biochemical analyses of the various protein components that make up this signaling pathway have identified a number of plausible molecular targets that are amenable to targeting by small molecules...
October 20, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28877076/disruption-of-the-with-no-lysine-kinase-ste20-proline-alanine-rich-kinase-pathway-reduces-the-hypertension-induced-by-angiotensin-ii
#11
Luz G Cervantes-Perez, Maria Castaneda-Bueno, Jose V Jimenez, Norma Vazquez, Lorena Rojas-Vega, Dario R Alessi, Norma A Bobadilla, Gerardo Gamba
OBJECTIVE: The hypertensive effect of angiotensin II (AngII), a peptide hormone, is dependent on its intrarenal actions and the activation of the renal Na-Cl cotransporter (NCC), by AngII requires integrity of the with no lysine kinase/STE20-proline alanine-rich kinase (WNK/SPAK) signaling pathway. Here, we analyzed if the integrity of the WNK/SPAK pathway is required for AngII infusion to induce arterial hypertension. METHODS: We tested the effect of AngII or aldosterone administration on the blood pressure and on pNCC/NCC ratio in SPAK knock-in mice in which the kinase and thus NCC cannot be activated by WNK kinases...
September 14, 2017: Journal of Hypertension
https://www.readbyqxmd.com/read/28818393/the-modulation-of-the-phosphorylation-status-of-nkcc1-in-organ-cultured-bovine-lenses-implications-for-the-regulation-of-fiber-cell-and-overall-lens-volume
#12
Irene Vorontsova, Paul J Donaldson, Zhiying Kong, Chiharu Wickremesinghe, Leo Lam, Julie C Lim
In previous work, we have shown the Sodium/Potassium/2 Chloride Cotransporter (NKCC1) to be a key effector of lens fiber cell volume regulation. Since others have shown that the activity of NKCC1 is regulated via its phosphorylation status, the purpose of this study was to investigate whether NKCC1 phosphorylation can be modulated in organ cultured bovine lenses, and to see how this relates to changes in lens wet weight. Western blotting was first used to confirm the expression of NKCC1, phosphorylated NKCC1 (NKCC1-P) and the regulatory kinases WNK/SPAK and phosphatases PP1/PP2A in bovine lenses at the protein level...
August 14, 2017: Experimental Eye Research
https://www.readbyqxmd.com/read/28771350/optimization-of-allosteric-with-no-lysine-wnk-kinase-inhibitors-and-efficacy-in-rodent-hypertension-models
#13
Ken Yamada, Julian Levell, Taeyong Yoon, Darcy Kohls, David Yowe, Dean F Rigel, Hidetomo Imase, Jun Yuan, Kayo Yasoshima, Keith DiPetrillo, Lauren Monovich, Lingfei Xu, Meicheng Zhu, Mitsunori Kato, Monish Jain, Neeraja Idamakanti, Paul Taslimi, Toshio Kawanami, Upendra A Argikar, Vidya Kunjathoor, Xiaoling Xie, Yukiko I Yagi, Yuki Iwaki, Zachary Robinson, Hyi-Man Park
The observed structure-activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compounds with a good balance of selectivity, cellular potency, and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies...
August 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28743496/wnk4-is-indispensable-for-the-pathogenesis-of-pseudohypoaldosteronism-type-ii-caused-by-mutant-klhl3
#14
Koichiro Susa, Eisei Sohara, Daiei Takahashi, Tomokazu Okado, Tatemitsu Rai, Shinichi Uchida
WNK-OSR1/SPAK-NCC signaling cascade is important for regulating salt balance and blood pressure. Activation of WNK-OSR1/SPAK-NaCl cotransporter (NCC) cascade increases sodium reabsorption in the kidney, leading to pseudohypoaldosteronism type II (PHA II) characterized by salt-sensitive hypertension and hyperkalemia. It has been previously demonstrated that the amount of phosphorylated and total NCC markedly decreased in WNK4(-/-) mice, indicating that WNK4 plays a major role for activation of OSR1/SPAK-NCC signaling...
September 23, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28679296/pharmacological-targeting-of-spak-kinase-in-disorders-of-impaired-epithelial-transport
#15
REVIEW
Jinwei Zhang, Jason K Karimy, Eric Delpire, Kristopher T Kahle
The mammalian SPS1-related proline/alanine-rich serine-threonine kinase SPAK (STK39) modulates ion transport across and between epithelial cells in response to environmental stimuli such osmotic stress and inflammation. Research over the last decade has established a central role for SPAK in the regulation of ion and water transport in the distal nephron, colonic crypts, and pancreatic ducts, and has implicated deregulated SPAK signaling in NaCl-sensitive hypertension, ulcerative colitis and Crohn's disease, and cystic fibrosis...
August 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28566208/development-of-wnk-signaling-inhibitors-as-a-new-class-of-antihypertensive-drugs
#16
Mari Ishigami-Yuasa, Yuko Watanabe, Takayasu Mori, Hiroyuki Masuno, Shinya Fujii, Eriko Kikuchi, Shinichi Uchida, Hiroyuki Kagechika
Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia and hypertension despite a normal glomerular filtration rate. Abnormal activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress-responsive kinase 1)/SPAK (STE20/SPS1-related proline/alanine-rich kinase) and NCC (NaCl cotransporter) results in characteristic salt-sensitive hypertension. Thus, inhibitors of the WNK-OSR1/SPAK-NCC cascade are candidates for a new class of antihypertensive drugs. In this study, we developed novel inhibitors of this signal cascade from the 9-aminoacridine lead compound 1, one of the hit compounds obtained by screening our chemical library for WNK-SPAK binding inhibitors...
July 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28560800/emerging-targets-of-diuretic-therapy
#17
REVIEW
C-J Cheng, A R Rodan, C-L Huang
Diuretics are commonly prescribed for treatment in patients with hypertension, edema, or heart failure. Studies on hypertensive and salt-losing disorders and on urea transporters have contributed to better understanding of mechanisms of renal salt and water reabsorption and their regulation. Proteins involved in the regulatory pathways are emerging targets for diuretic and aquaretic therapy. Integrative high-throughput screening, protein structure analysis, and chemical modification have identified promising agents for preclinical testing in animals...
September 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28522431/wnk1-and-p38-mapk-distribution-in-ionocytes-and-accessory-cells-of-euryhaline-teleost-fish-implies-ionoregulatory-function
#18
W S Marshall, R R F Cozzi, M Spieker
Ionocytes of euryhaline teleost fish secrete NaCl, under regulation by serine and threonine kinases, including with-no-lysine kinase (WNK1) and p38 mitogen-activated protein kinase (MAPK). Mummichogs (Fundulus heteroclitus L.) were acclimated to freshwater (FW), full strength seawater (SW) and hypersaline conditions (2SW). Immunocytochemistry of ionocytes in opercular epithelia of fish acclimated to SW and 2SW revealed that WNK1-anti-pT58 phosphoantibody localized strongly to accessory cells and was present in the cytosol of ionocytes, close to cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane and the sodium potassium 2 chloride cotransporter (NKCC) in the basolateral membrane...
July 15, 2017: Biology Open
https://www.readbyqxmd.com/read/28498874/soluble-bone-derived-osteopontin-promotes-migration-and-stem-like-behavior-of-breast-cancer-cells
#19
Graciella M Pio, Ying Xia, Matthew M Piaseczny, Jenny E Chu, Alison L Allan
Breast cancer is a leading cause of cancer death in women, with the majority of these deaths caused by metastasis to distant organs. The most common site of breast cancer metastasis is the bone, which has been shown to provide a rich microenvironment that supports the migration and growth of breast cancer cells. Additionally, growing evidence suggests that breast cancer cells that do successfully metastasize have a stem-like phenotype including high activity of aldehyde dehydrogenase (ALDH) and/or a CD44+CD24- phenotype...
2017: PloS One
https://www.readbyqxmd.com/read/28442491/constitutively-active-spak-causes-hyperkalemia-by-activating-ncc-and-remodeling-distal-tubules
#20
P Richard Grimm, Richard Coleman, Eric Delpire, Paul A Welling
Aberrant activation of with no lysine (WNK) kinases causes familial hyperkalemic hypertension (FHHt). Thiazide diuretics treat the disease, fostering the view that hyperactivation of the thiazide-sensitive sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT) is solely responsible. However, aberrant signaling in the aldosterone-sensitive distal nephron (ASDN) and inhibition of the potassium-excretory renal outer medullary potassium (ROMK) channel have also been implicated. To test these ideas, we introduced kinase-activating mutations after Lox-P sites in the mouse Stk39 gene, which encodes the terminal kinase in the WNK signaling pathway, Ste20-related proline-alanine-rich kinase (SPAK)...
September 2017: Journal of the American Society of Nephrology: JASN
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