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https://www.readbyqxmd.com/read/29602832/intracellular-chloride-and-scaffold-protein-mo25-cooperatively-regulate-transepithelial-ion-transport-through-wnk-signaling-in-the-malpighian-tubule
#1
Qifei Sun, Yipin Wu, Sima Jonusaite, John M Pleinis, John M Humphreys, Haixia He, Jeffrey N Schellinger, Radha Akella, Drew Stenesen, Helmut Krämer, Elizabeth J Goldsmith, Aylin R Rodan
Background With No Lysine kinase (WNK) signaling regulates mammalian renal epithelial ion transport to maintain electrolyte and BP homeostasis. Our previous studies showed a conserved role for WNK in the regulation of transepithelial ion transport in the Drosophila Malpighian tubule. Methods Using in vitro assays and transgenic Drosophila lines, we examined two potential WNK regulators, chloride ion and the scaffold protein mouse protein 25 (Mo25), in the stimulation of transepithelial ion flux. Results In vitro , autophosphorylation of purified Drosophila WNK decreased as chloride concentration increased...
May 2018: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/29596900/role-of-nitric-oxide-and-wnk-spak-osr1-kcc2-signaling-in-daily-changes-in-gabaergic-inhibition-in-the-rat-dorsal-raphe-neurons
#2
Mi Jung Kim, Hye Jin Yang, Younghoon Kim, Insug Kang, Sung Soo Kim, Young-Wuk Cho
Serotonergic neurons in the dorsal raphe nucleus (DRN) act as wake-inducing neurons in the sleep-wake cycle and are controlled by gamma-aminobutyric acid (GABA) synaptic inputs. We investigated daily changes in GABAergic inhibition of the rat DRN neurons and the role of nitric oxide (NO) and cation-chloride co-transporters in the GABAergic action. Neuronal NO synthase (nNOS) was co-expressed in 74% of serotonergic DRN neurons and nNOS expression was higher during daytime (the sleep cycle) than that during nighttime (the wake cycle)...
March 27, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29581290/osr1-regulates-a-subset-of-inward-rectifier-potassium-channels-via-a-binding-motif-variant
#3
Clinton A Taylor, Sung-Wan An, Sachith Gallolu Kankanamalage, Steve Stippec, Svetlana Earnest, Ashesh T Trivedi, Jonathan Zijiang Yang, Hamid Mirzaei, Chou-Long Huang, Melanie H Cobb
The with-no-lysine (K) (WNK) signaling pathway to STE20/SPS1-related proline- and alanine-rich kinase (SPAK) and oxidative stress-responsive 1 (OSR1) kinase is an important mediator of cell volume and ion transport. SPAK and OSR1 associate with upstream kinases WNK 1-4, substrates, and other proteins through their C-terminal domains which interact with linear R-F-x-V/I sequence motifs. In this study we find that SPAK and OSR1 also interact with similar affinity with a motif variant, R-x-F-x-V/I. Eight of 16 human inward rectifier K+ channels have an R-x-F-x-V motif...
April 10, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29576087/expression-of-oswnk9-in-arabidopsis-conferred-tolerance-to-salt-and-drought-stress
#4
Rakesh Manuka, Ankush Ashok Saddhe, Kundan Kumar
With No Lysine (WNK) kinase belongs to ser/thr protein kinase group in which conserved catalytic lysine (K) residue of subdomain II is shifted to subdomain I. In this study, we cloned full-length coding region of WNK9 from Oryza sativa (OsWNK9) and performed in silico studies to confirm the presence of all kinase signature regulatory elements. The transcript analysis revealed that OsWNK9 was strongly down regulated under salinity, drought and ABA stress in shoots. Constitutive expression of OsWNK9 in Arabidopsis thaliana imparted increased tolerance to salt, drought, and ABA stress...
May 2018: Plant Science: An International Journal of Experimental Plant Biology
https://www.readbyqxmd.com/read/29510178/metformin-increases-urinary-sodium-excretion-by-reducing-phosphorylation-of-the-sodium-chloride-cotransporter
#5
Hiroko Hashimoto, Naohiro Nomura, Wakana Shoda, Kiyoshi Isobe, Hiroaki Kikuchi, Kouhei Yamamoto, Takuya Fujimaru, Fumiaki Ando, Takayasu Mori, Tomokazu Okado, Tatemitsu Rai, Shinichi Uchida, Eisei Sohara
OBJECTIVE: Metformin is an antidiabetic drug that is widely used to treat patients with diabetes mellitus. Recent studies have reported that treatment with metformin not only improved blood glucose levels but also reduced blood pressure. However, it remains unclear how metformin reduces blood pressure. We hypothesized that metformin affects sodium reabsorption in the kidneys. METHODS: Urinary sodium excretion and expression of renal sodium transporters were examined in 8-week-old male C57BL/6 mice with acute and chronic treatment of metformin...
March 3, 2018: Metabolism: Clinical and Experimental
https://www.readbyqxmd.com/read/29494638/glycogen-synthase-kinase-3%C3%A3-functions-as-a-positive-effector-in-the-wnk-signaling-pathway
#6
Atsushi Sato, Hiroshi Shibuya
The with no lysine (WNK) protein kinase family is conserved among many species. Some mutations in human WNK gene are associated with pseudohypoaldosteronism type II, a form of hypertension, and hereditary sensory and autonomic neuropathy type 2A. In kidney, WNK regulates the activity of STE20/SPS1-related, proline alanine-rich kinase and/or oxidative-stress responsive 1, which in turn regulate ion co-transporters. The misregulation of this pathway is involved in the pathogenesis of pseudohypoaldosteronism type II...
2018: PloS One
https://www.readbyqxmd.com/read/29473325/cheminformatics-analysis-of-dynamic-wnk-inhibitor-interactions
#7
Melaine A Kuenemann, Denis Fourches
The With-No-Lysine (WNK) serine/threonine kinase family constitutes a unique and distinctive branch of the kinome. The four proteins of this family (WNK1/2/3/4) are involved in blood pressure regulation, body fluid, and electrolyte homeostasis. Herein, we modeled and analyzed the binding modes of all publicly-available small orthosteric and allosteric binders (including WNK463 and WNK467) experimentally tested towards any of the WNK family member. To do so, we relied on state-of-the-art cheminformatics approaches including structure-based molecular docking and molecular dynamics simulations...
February 23, 2018: Molecular Informatics
https://www.readbyqxmd.com/read/29459793/consequences-of-spak-inactivation-on-hyperkalemic-hypertension-caused-by-wnk1-mutations-evidence-for-differential-roles-of-wnk1-and-wnk4
#8
Chloé Rafael, Christelle Soukaseum, Véronique Baudrie, Perrine Frère, Juliette Hadchouel
Mutations of the gene encoding WNK1 [With No lysine (K) kinase 1] or WNK4 cause Familial Hyperkalemic Hypertension (FHHt). Previous studies have shown that the activation of SPAK (Ste20-related Proline/Alanine-rich Kinase) plays a dominant role in the development of FHHt caused by WNK4 mutations. The implication of SPAK in FHHt caused by WNK1 mutation has never been investigated. To clarify this issue, we crossed WNK1+/FHHt mice with SPAK knock-in mice in which the T-loop Thr243 residue was mutated to alanine to prevent activation by WNK kinases...
February 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29392534/overexpression-of-wnk1-in-pomc-expressing-neurons-reduces-weigh-gain-via-wnk4-mediated-degradation-of-kir6-2
#9
Woo Young Chung, Jung Woo Han, Woon Heo, Min Goo Lee, Joo Young Kim
"With no lysine" (WNK) kinases have been shown to regulate various ion transporters in various tissues, but studies on the function of WNK kinases in the brain have been limited. In this study, we discovered that WNK1 and WNK4 in POMC-expressing neuronal cells in WNK1 overexpressed transgenic mice (WNK1 TG) decrease appetite via degradation of Kir6.2. Weight gain after 20 weeks of age was delayed in WNK1 TG mice as a result of reduced food intake. Expression of WNK1 and proopiomelanocortin (POMC) was higher in POMC-expressing neurons in the hypothalamus of WNK1 TG mice than in WT mice...
February 1, 2018: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29384416/differential-roles-of-wnk4-in-regulation-of-ncc-in-vivo
#10
Yih-Sheng Yang, Jian Xie, Sung-Sen Yang, Shih-Hua Lin, Chou-Long Huang
The Na+-Cl- cotransporter (NCC) in distal convoluted tubule (DCT) plays important roles in renal NaCl reabsorption. Current hypothesis for the mechanism of regulation of NCC focuses on WNK4 and intracellular Cl- concentration ([Cl-]i). WNK kinases bind Cl- and Cl- binding decreases the catalytic activity. It is believed that hypokalemia under low K+ intake decreases [Cl-]i to activate WNK4, which thereby phosphorylates and stimulates NCC through activation of SPAK. However, increased NCC activity and apical NaCl entry would mitigate the fall in [Cl-]i...
January 31, 2018: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29361671/mechanisms-and-controversies-in-mutant-cul3-mediated-familial-hyperkalemic-hypertension
#11
Mohammed Zubaerul Ferdaus, James A McCormick
Autosomal dominant mutations in Cullin3 (Cul3) cause the most severe form of Familial Hyperkalemic Hypertension (FHHt). Cul3 mutations cause skipping of exon 9 which results in an internal deletion of 57 amino acids from the CUL3 protein (CUL3-∆9). The precise mechanism by which this altered form of CUL3 causes FHHt is controversial. CUL3 is a member of the Cullin-Ring ubiquitin Ligase (CRL) family which mediates ubiquitination and thus degradation of cellular proteins including With-no-lysine [K] kinases (WNKs)...
January 17, 2018: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29329909/the-signaling-role-for-chloride-in-the-bidirectional-communication-between-neurons-and-astrocytes
#12
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
#13
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 with-no-lysine kinase (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 β-subunit of ClC-K...
February 28, 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
#14
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
#15
Cary R Boyd-Shiwarski, Daniel J Shiwarski, Ankita Roy, Hima N Namboodiri, Lubika J Nkashama, 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." Although 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...
February 15, 2018: 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
#16
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...
February 2018: 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
#17
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 Kir 4.1/5.1 (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 Kir 4.1/5.1 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 Kir 4...
February 2018: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/29092909/-n-ethylmaleimide-increases-kcc2-cotransporter-activity-by-modulating-transporter-phosphorylation
#18
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
K+ /Cl- cotransporter 2 (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 (GABAA ) receptors, 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...
December 29, 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
#19
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
#20
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
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