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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
Tao Yang, Kai Zhao, Haifeng Shu, Xin Chen, Jingmin Cheng, Song Li, Ziyi Zhao, Yongqin Kuang, Sixun Yu
Neuronal regeneration and axonal regrowth mechanisms in the injured mammalian central nervous system are largely unknown. As part of a major pathway for inhibiting axonal regeneration, activated neuronal glycosylphosphatidylinositol-anchored Nogo receptor (NgR) interacts with LINGO-1 and p75NTR to form a complex at the cell surface. However, it was found in our previous report that upregulation of NgR stimulated by injury plays a key role in neuronal regeneration in the neonatal cortex freeze-lesion model, but its downstream signalling remains elusive...
June 14, 2017: Neuroreport
Ying Qiao, Chansonette Badduke, Flamingo Tang, David Cowieson, Sally Martell, Suzanne M E Lewis, Maria S Peñaherrera, Wendy P Robinson, Allen Volchuk, Evica Rajcan-Separovic
Recurrent microduplications/microdeletions of 1q21.1 are characterized by variable phenotypes ranging from normal development to developmental delay (DD) and congenital anomalies. Their interpretation is challenging especially in families with affected and unaffected carriers. We used whole exome sequencing (WES) to look for sequence variants in two male probands with inherited 1q21.1 CNVs that could explain their more severe phenotypes. One proband had a 1q21.1 deletion transmitted from maternal grandmother, while the other had a paternal duplication...
May 5, 2017: American Journal of Medical Genetics. Part A
Mohammad Iqbal H Bhuiyan, Shanshan Song, Hui Yuan, Gulnaz Begum, Julia Kofler, Kristopher T Kahle, Sung-Sen Yang, Shih-Hua Lin, Seth L Alper, Arohan R Subramanya, Dandan Sun
With-no-lysine kinase (WNK) and Na+ -K+ -2Cl- cotransporter 1 (NKCC1) are involved in the pathogenesis of hypertension. In this study, we investigated the WNK-NKCC1 signaling pathway in spontaneously hypertensive rats (SHR) and their associated susceptibility to stroke injury. Basal NKCC1 protein levels were higher in SHR than in normotensive Wistar Kyoto (WKY) rat brains. After inducing ischemic stroke, adult male WKY and SHR received either saline or NKCC1 inhibitor bumetanide (10 mg/kg/day, i.p.) starting at 3-h post-reperfusion...
August 2017: Journal of Cerebral Blood Flow and Metabolism
Jinwei Zhang, Geng Gao, Gulnaz Begum, Jinhua Wang, Arjun R Khanna, Boris E Shmukler, Gerrit M Daubner, Paola de Los Heros, Paul Davies, Joby Varghese, Mohammad Iqbal H Bhuiyan, Jinjing Duan, Jin Zhang, Daniel Duran, Seth L Alper, Dandan Sun, Stephen J Elledge, Dario R Alessi, Kristopher T Kahle
Cell volume homeostasis requires the dynamically regulated transport of ions across the plasmalemma. While the ensemble of ion transport proteins involved in cell volume regulation is well established, the molecular coordinators of their activities remain poorly characterized. We utilized a functional kinomics approach including a kinome-wide siRNA-phosphoproteomic screen, a high-content kinase inhibitor screen, and a kinase trapping-Orbitrap mass spectroscopy screen to systematically identify essential kinase regulators of KCC3 Thr(991)/Thr(1048) phosphorylation - a key signaling event in cell swelling-induced regulatory volume decrease (RVD)...
October 26, 2016: Scientific Reports
Dexuan Wang, Yiqian Zhang, Jinhua Han, Shufang Pan, Ning Xu, Xiuyan Feng, Zhizhi Zhuang, Courtney Caroti, Jieqiu Zhuang, Robert S Hoover, Dingying Gu, Qiyi Zeng, Hui Cai
BACKGROUND: WNK kinase is a serine/threonine kinase that plays an important role in normal blood pressure homeostasis. WNK3 was previously found to enhance the activity of sodium chloride cotransporter (NCC) in Xenopus oocyte. However, the mechanism through which it works remains unclear. METHODS: Using overexpression and siRNA knock-down techniques, the effects of WNK3 on NCC in both Cos-7 and mouse distal convoluted cells were analyzed by Western blot. RESULTS: We found that WNK3 significantly increased NCC protein expression in a dose-dependent manner...
2016: Nephron
Dexuan Wang, Shufang Pan, Yixiao Xu, Xiaohua Ye, Xiaobi Ren, Qiyi Zeng
No abstract text is available yet for this article.
November 2016: Science China. Life Sciences
Bor Luen Tang
Members of With-no-lysine (WNK) family of serine-threonine kinase are key regulators of chloride ion transport in diverse cell types, controlling the activity and the surface expression of cation-chloride (Na(+)/K(+)-Cl(-)) co-transporters. Mutations in WNK1 and WNK4 are linked to a hereditary form of hypertension, and WNKs have been extensively investigated pertaining to their roles in renal epithelial ion homeostasis. However, some members of the WNK family and their splice isoforms are also expressed in the mammalian brain, and have been implicated in aspects of hereditary neuropathy as well as neuronal and glial survival...
July 2016: Brain Research Bulletin
Hanshu Zhao, Rachel Nepomuceno, Xin Gao, Lesley M Foley, Shaoxia Wang, Gulnaz Begum, Wen Zhu, Victoria M Pigott, Lindsay M Falgoust, Kristopher T Kahle, Sung-Sen Yang, Shih-Hua Lin, Seth L Alper, T Kevin Hitchens, Shaoshan Hu, Zhongling Zhang, Dandan Sun
The WNK-SPAK kinase signaling pathway controls renal NaCl reabsorption and systemic blood pressure by regulating ion transporters and channels. A WNK3-SPAK complex is highly expressed in brain, but its function in this organ remains unclear. Here, we investigated the role of this kinase complex in brain edema and white matter injury after ischemic stroke. Wild-type, WNK3 knockout, and SPAK heterozygous or knockout mice underwent transient middle cerebral artery occlusion. One cohort of mice underwent magnetic resonance imaging...
February 2017: Journal of Cerebral Blood Flow and Metabolism
Gulnaz Begum, Hui Yuan, Kristopher T Kahle, Liaoliao Li, Shaoxia Wang, Yejie Shi, Boris E Shmukler, Sung-Sen Yang, Shih-Hua Lin, Seth L Alper, Dandan Sun
BACKGROUND AND PURPOSE: WNK kinases, including WNK3, and the associated downstream Ste20/SPS1-related proline-alanine-rich protein kinase (SPAK) and oxidative stress responsive 1 (OSR1) kinases, comprise an important signaling cascade that regulates the cation-chloride cotransporters. Ischemia-induced stimulation of the bumetanide-sensitive Na(+)-K(+)-Cl(-) cotransporter (NKCC1) plays an important role in the pathophysiology of experimental stroke, but the mechanism of its regulation in this context is unknown...
July 2015: Stroke; a Journal of Cerebral Circulation
Crystal A West, Alicia A McDonough, Shyama M E Masilamani, Jill W Verlander, Chris Baylis
Pregnancy is characterized by plasma volume expansion due to Na(+) retention, driven by aldosterone. The aldosterone-responsive epithelial Na(+) channel is activated in the kidney in pregnancy. In the present study, we investigated the aldosterone-responsive Na(+)-Cl(-) cotransporter (NCC) in mid- and late pregnant rats compared with virgin rats. We determined the abundance of total NCC, phosphorylated NCC (pNCC; pT53, pS71 and pS89), phosphorylated STE20/SPS-1-related proline-alanine-rich protein kinase (pSPAK; pS373), and phosphorylated oxidative stress-related kinase (pOSR1; pS325) in the kidney cortex...
July 1, 2015: American Journal of Physiology. Renal Physiology
Moko Zeniya, Nobuhisa Morimoto, Daiei Takahashi, Yutaro Mori, Takayasu Mori, Fumiaki Ando, Yuya Araki, Yuki Yoshizaki, Yuichi Inoue, Kiyoshi Isobe, Naohiro Nomura, Katsuyuki Oi, Hidenori Nishida, Sei Sasaki, Eisei Sohara, Tatemitsu Rai, Shinichi Uchida
Recently, the kelch-like protein 3 (KLHL3)-Cullin3 complex was identified as an E3 ubiquitin ligase for with no lysine (WNK) kinases, and the impaired ubiquitination of WNK4 causes pseudohypoaldosteronism type II (PHAII), a hereditary hypertensive disease. However, the involvement of WNK kinase regulation by ubiquitination in situations other than PHAII has not been identified. Previously, we identified the WNK3-STE20/SPS1-related proline/alanine-rich kinase-Na/K/Cl cotransporter isoform 1 phosphorylation cascade in vascular smooth muscle cells and found that it constitutes an important mechanism of vascular constriction by angiotensin II (AngII)...
September 2015: Journal of the American Society of Nephrology: JASN
María Chávez-Canales, Chong Zhang, Christelle Soukaseum, Erika Moreno, Diana Pacheco-Alvarez, Emmanuelle Vidal-Petiot, María Castañeda-Bueno, Norma Vázquez, Lorena Rojas-Vega, Nicholas P Meermeier, Shaunessy Rogers, Xavier Jeunemaitre, Chao-Ling Yang, David H Ellison, Gerardo Gamba, Juliette Hadchouel
The with-no-lysine (K) kinases, WNK1 and WNK4, are key regulators of blood pressure. Their mutations lead to familial hyperkalemic hypertension (FHHt), associated with an activation of the Na-Cl cotransporter (NCC). Although it is clear that WNK4 mutants activate NCC via Ste20 proline-alanine-rich kinase, the mechanisms responsible for WNK1-related FHHt and alterations in NCC activity are not as clear. We tested whether WNK1 modulates NCC through WNK4, as predicted by some models, by crossing our recently developed WNK1-FHHt mice (WNK1(+/FHHt)) with WNK4(-/-) mice...
November 2014: Hypertension
Dagmara Lagnaz, Juan Pablo Arroyo, María Chávez-Canales, Norma Vázquez, Federica Rizzo, Alessia Spirlí, Anne Debonneville, Olivier Staub, Gerardo Gamba
The serine/threonine kinase WNK3 and the ubiquitin-protein ligase NEDD4-2 are key regulators of the thiazide-sensitive Na+-Cl- cotransporter (NCC), WNK3 as an activator and NEDD2-4 as an inhibitor. Nedd4-2 was identified as an interacting partner of WNK3 through a glutathione-S-transferase pull-down assay using the N-terminal domain of WNK3, combined with LC-MS/MS analysis. This was validated by coimmunoprecipitation of WNK3 and NEDD4-2 expressed in HEK293 cells. Our data also revealed that the interaction between Nedd4-2 and WNK3 does not involve the PY-like motif found in WNK3...
August 1, 2014: American Journal of Physiology. Renal Physiology
María Castañeda-Bueno, Luz Graciela Cervantes-Perez, Lorena Rojas-Vega, Isidora Arroyo-Garza, Norma Vázquez, Erika Moreno, Gerardo Gamba
Modulation of Na(+)-Cl(-) cotransporter (NCC) activity is essential to adjust K(+) excretion in the face of changes in dietary K(+) intake. We used previously characterized genetic mouse models to assess the role of Ste20-related proline-alanine-rich kinase (SPAK) and with-no-lysine kinase (WNK)4 in the modulation of NCC by K(+) diets. SPAK knockin and WNK4 knockout mice were placed on normal-, low-, or high-K(+)-citrate diets for 4 days. The low-K(+) diet decreased and high-K(+) diet increased plasma aldosterone levels, but both diets were associated with increased phosphorylation of NCC (phospho-NCC, Thr(44)/Thr(48)/Thr(53)) and phosphorylation of SPAK/oxidative stress responsive kinase 1 (phospho-SPAK/OSR1, Ser(383)/Ser(325))...
June 15, 2014: American Journal of Physiology. Renal Physiology
Zesergio Melo, Paola de los Heros, Silvia Cruz-Rangel, Norma Vázquez, Norma A Bobadilla, Herminia Pasantes-Morales, Dario R Alessi, Adriana Mercado, Gerardo Gamba
The K(+):Cl(-) cotransporter (KCC) activity is modulated by phosphorylation/dephosphorylation processes. In isotonic conditions, KCCs are inactive and phosphorylated, whereas hypotonicity promotes their dephosphorylation and activation. Two phosphorylation sites (Thr-991 and Thr-1048) in KCC3 have been found to be critical for its regulation. However, here we show that the double mutant KCC3-T991A/T1048A could be further activated by hypotonicity, suggesting that additional phosphorylation site(s) are involved...
November 1, 2013: Journal of Biological Chemistry
Moko Zeniya, Eisei Sohara, Satomi Kita, Takahiro Iwamoto, Koichiro Susa, Takayasu Mori, Katsuyuki Oi, Motoko Chiga, Daiei Takahashi, Sung-Sen Yang, Shih-Hua Lin, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
Na-K-Cl cotransporter isoform 1 (NKCC1) is involved in the regulation of vascular smooth muscle cell contraction. Recently, the with-no-lysine kinase (WNK)-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NKCC1 phosphorylation cascade in vascular smooth muscle cells was found to be important in the regulation of vascular tone. In this study, we investigated whether the WNK-SPAK-NKCC1 cascade in mouse aortic tissue is regulated by dietary salt intake and the mechanisms responsible. Phosphorylation of SPAK and NKCC1 was significantly reduced in the aorta in high-salt-fed mice and was increased in the aorta in low-salt-fed mice, indicating that the WNK-SPAK-NKCC1 phosphorylation cascade in the aorta was indeed regulated by dietary salt intake...
November 2013: Hypertension
Daiei Takahashi, Takayasu Mori, Mai Wakabayashi, Yutaro Mori, Koichiro Susa, Moko Zeniya, Eisei Sohara, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
Mutations in the WNK1 and WNK4 genes result in an inherited hypertensive disease, pseudohypoaldosteronism type II (PHAII). Recently, the KLHL3 and Cullin3 genes were also identified as responsible genes for PHAII. Although we have reported that WNK4 is a substrate for the KLHL3-Cullin3 E3 ligase complex, it is not clear whether all of the WNK isoforms are regulated only by KLHL3. To explore the interaction of WNKs and other Kelch-like proteins, we focused on KLHL2 (Mayven), a human homolog of Drosophila Kelch that shares the highest similarity with KLHL3...
August 2, 2013: Biochemical and Biophysical Research Communications
Chien-Te Lee, Yeong-Hau H Lien, Li-Wen Lai, Hwee-Yeong Ng, Terry Ting-Yu Chiou, Hung-Chun Chen
BACKGROUND: The renal distal tubule fine-tunes renal epithelial calcium transport. Dietary intake of salt and fluid varies day-to-day and the kidney adapts accordingly to maintain homeostasis. The alternations in salt and fluid balance affect calcium and magnesium transport in the distal tubule, but the mechanisms are not fully understood. METHODS: Sprague-Dawley rats were grouped into high-salt, low-salt and dehydration treatment. Daily intake, water consumption and urine output were recorded...
2012: Nephron. Physiology
Zhaohuan Zhang, Xiaohui Xu, Zhenghua Xiang, Zhongwang Yu, Jifeng Feng, Cheng He
LINGO-1 is a functional component of the Nogo receptor 1 · p75(NTR) · LINGO-1 and Nogo receptor 1 · TAJ (TNFRSF19/TROY)·LINGO-1 signaling complexes. It has recently been shown that LINGO-1 antagonists significantly improve neuronal survival after neural injury. However, the mechanism by which LINGO-1 signaling influences susceptibility to apoptosis remains unknown. In an effort to better understand how LINGO-1 regulates these signaling pathways, we used an established model of serum deprivation (SD) to induce neuronal apoptosis...
April 26, 2013: Journal of Biological Chemistry
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