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Clive P Morgan, Hongyu Zhao, Meredith LeMasurier, Wei Xiong, Bifeng Pan, Piotr Kazmierczak, Matthew R Avenarius, Michael Bateschell, Ruby Larisch, Anthony J Ricci, Ulrich Müller, Peter G Barr-Gillespie
Hair cells of the inner ear transduce mechanical stimuli like sound or head movements into electrical signals, which are propagated to the central nervous system. The hair-cell mechanotransduction channel remains unidentified. We tested whether three transient receptor channel (TRP) family members, TRPV6, TRPM6 and TRPM7, were necessary for transduction. TRPV6 interacted with USH1C (harmonin), a scaffolding protein that participates in transduction. Using a cysteine-substitution knock-in mouse line and methanethiosulfonate (MTS) reagents selective for this allele, we found that inhibition of TRPV6 had no effect on transduction in mouse cochlear hair cells...
2018: Frontiers in Cellular Neuroscience
Neil Bate, Rachel E Caves, Simon P Skinner, Ben T Goult, Jaswir Basran, John S Mitcheson, Geerten W Vuister
The paralogues TRPV5 and TRPV6 belong to the vanilloid subfamily of the Transient Receptor Potential (TRP) superfamily of ion channels and both play an important role in overall Ca2+ homeostasis. The functioning of the channels centres on a tightly controlled Ca2+ -dependent feedback mechanism where the direct binding of the universal Ca2+ -binding protein calmodulin (CaM) to the channel's C-terminal tail is required for channel inactivation. We have investigated this interaction at the atomic level and propose that under basal cellular [Ca2+] CaM is constitutively bound to the channel's C-tail via CaM C-lobe only contacts...
March 5, 2018: Biochemistry
Jin Yong An, Changhwan Ahn, Hee Young Kang, Eui-Bae Jeung
Calcium is important for physiological functioning in many tissues and is essential in mucus secretion and muscle contraction. Intracellular concentrations of calcium are regulated by calcium-related proteins such as TRPV4, TRPV6, CaBP-9k, NCX1, and PMCA1. In this study, the relationship between secretion of pulmonary mucus and calcium regulation was investigated. To confirm the effect of steroid hormones, immature mice were injected with estrogen (E2) or progesterone (P4) and mature mice were injected with dexamethasone (DEX)...
February 15, 2018: American Journal of Physiology. Lung Cellular and Molecular Physiology
Nguyen Thi Xuan, Nong Van Hai
Klotho (KL) encodes a single-pass transmembrane protein and is predominantly expressed in the kidney, parathyroid glands, and choroid plexus. Genetic studies on the KL gene have revealed that DNA hypermethylation is one of the major risk factors for aging, diseases, and cancer. Besides, KL exerts anti-inflammatory and anti-tumor effects by regulating signaling pathways and the expression of target genes. KL participates in modulation of the insulin/insulin-like growth factor-1 (IGF-1) signaling, which induces the growth hormone (GH) secretion...
January 2018: Iranian Journal of Basic Medical Sciences
He Song, Ming Dong, Jianping Zhou, Weiwei Sheng, Xin Li, Wei Gao
In this study, we aimed to clarify the expression and biological functions of TRPV6 in human pancreatic cancer (PC) tissue and pancreatic cancer (PC) cell lines. TRPV6 was up-regulated in the primary cancer tissues from pancreatic cancer (PC) patients. TRPV6 may regulate multiple proteins related to apoptosis, cell cycle and metastasis pathways. Silencing TRPV6 significantly inhibited invasion, proliferation and migration and induced apoptosis and cell cycle arrest. TRPV6 plays a promising role of an oncogene in pancreatic carcinogenesis and represents the new potential biomarker for PC...
January 15, 2018: Oncology Reports
Luke L McGoldrick, Appu K Singh, Kei Saotome, Maria V Yelshanskaya, Edward C Twomey, Robert A Grassucci, Alexander I Sobolevsky
Calcium-selective transient receptor potential vanilloid subfamily member 6 (TRPV6) channels play a critical role in calcium uptake in epithelial tissues. Altered TRPV6 expression is associated with a variety of human diseases, including cancers. TRPV6 channels are constitutively active and their open probability depends on the lipidic composition of the membrane in which they reside; it increases substantially in the presence of phosphatidylinositol 4,5-bisphosphate. Crystal structures of detergent-solubilized rat TRPV6 in the closed state have previously been solved...
January 11, 2018: Nature
Shichen Xu, Li Zhang, Xian Cheng, Huixin Yu, Jiandong Bao, Rongrong Lu
Capsaicin (CAP), a potent transient receptor potential vanilloid type 1 (TRPV1) agonist, is a major ingredient of red pepper. Recently, capsaicin has attracted increasing attention owing to its multiple biological activities. However, the anticancer effects of capsaicin against various types of cancers, especially on thyroid carcinoma, have not been completely elucidated. TRPV1, which can be activated by capsaicin, plays a key role in many biological and physiological processes. In the present study, the anticancer properties of capsaicin against papillary thyroid cancer BCPAP cells were investigated...
January 24, 2018: Food & Function
Shahab Bahadoran, Amir Dehghani Samani, Hossein Hassanpour
Heat stress is a problem in laying hens as it decreases egg quality by decreasing eggshell mineralization. Heat stress alters gene expression, hence our aim was to investigate effects of heat stress on gene expression of ion transport elements involving in uterine mineralization (TRPV6, CALB1, ITPR3, SCNN1G, SLC4A4, KCNJ15, SLC4A9, and CLCN2) by real time quantitative PCR. Forty 23-week-old White Leghorn laying hens were housed in two rooms. The control group (n = 20) was maintained at 21-23 °C, and the heat stress group (n = 20) was exposed to 36-38 °C for 8 weeks...
November 8, 2017: Stress: the International Journal on the Biology of Stress
Mahendra Awale, Ricardo Visini, Daniel Probst, Josep Arús-Pous, Jean-Louis Reymond
Chemical space describes all possible molecules as well as multi-dimensional conceptual spaces representing the structural diversity of these molecules. Part of this chemical space is available in public databases ranging from thousands to billions of compounds. Exploiting these databases for drug discovery represents a typical big data problem limited by computational power, data storage and data access capacity. Here we review recent developments of our laboratory, including progress in the chemical universe databases (GDB) and the fragment subset FDB-17, tools for ligand-based virtual screening by nearest neighbor searches, such as our multi-fingerprint browser for the ZINC database to select purchasable screening compounds, and their application to discover potent and selective inhibitors for calcium channel TRPV6 and Aurora A kinase, the polypharmacology browser (PPB) for predicting off-target effects, and finally interactive 3D-chemical space visualization using our online tools WebDrugCS and WebMolCS...
October 25, 2017: Chimia
Qiao Li, Xingkai Zhao, Shujie Wang, Zhenlei Zhou
Estrogen regulates the calcium homeostasis in hens, but the mechanisms involved are still unclear fully. In this study, we investigated whether letrozole (LZ) induced low estrogen levels affected the calcium absorption and transport in layers. In the duodenum, we observed a significant decrease of mRNA expressions of Calbindin-28k (CaBP-28k) and plasma membrane Ca(2+)-ATPase (PMCA 1b) while CaBP-28k protein expression was declined in birds with LZ treatment, and the mRNA levels of duodenal transient receptor potential vanilloid 6 (TRPV6) and Na(+)/Ca(2+) exchanger 1 (NCX1) were not affected...
January 1, 2018: General and Comparative Endocrinology
Jie Zheng, Mi Ra Chang, Ryan E Stites, Yong Wang, John B Bruning, Bruce D Pascal, Scott J Novick, Ruben D Garcia-Ordonez, Keith R Stayrook, Michael J Chalmers, Jeffrey A Dodge, Patrick R Griffin
The vitamin D receptor/retinoid X receptor-α heterodimer (VDRRXRα) regulates bone mineralization via transcriptional control of osteocalcin (BGLAP) gene and is the receptor for 1α,25-dihydroxyvitamin D3 (1,25D3). However, supra-physiological levels of 1,25D3 activates the calcium-regulating gene TRPV6 leading to hypercalcemia. An approach to attenuate this adverse effect is to develop selective VDR modulators (VDRMs) that differentially activate BGLAP but not TRPV6. Here we present structural insight for the action of a VDRM compared with agonists by employing hydrogen/deuterium exchange...
October 13, 2017: Nature Communications
Wang Zheng, Ruikun Hu, Ruiqi Cai, Laura Hofmann, Qiaolin Hu, Mohammad Fatehi, Wentong Long, Tim Kong, Jingfeng Tang, Peter Light, Veit Flockerzi, Ying Cao, Xing-Zhen Chen
Transient receptor potential (TRP) channels, subdivided into 6 subfamilies in mammals, have essential roles in sensory physiology. They respond to remarkably diverse stimuli, comprising thermal, chemical, and mechanical modalities, through opening or closing of channel gates. In this study, we systematically substituted the hydrophobic residues within the distal fragment of pore-lining helix S6 with hydrophilic residues and, based on Xenopus oocyte and mammalian cell electrophysiology and a hydrophobic gate theory, identified hydrophobic gates in TRPV6/V5/V4/C4/M8...
September 28, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Appu K Singh, Kei Saotome, Alexander I Sobolevsky
Tetrameric ion channels have either swapped or non-swapped arrangements of the S1-S4 and pore domains. Here we show that mutations in the transmembrane domain of TRPV6 can result in conversion from a domain-swapped to non-swapped fold. These results reveal structural determinants of domain swapping and raise the possibility that a single ion channel subtype can fold into either arrangement in vivo, affecting its function in normal or disease states.
September 6, 2017: Scientific Reports
Zongtao Lin, Hao Chen, Anna Y Belorusova, John C Bollinger, Edith K Y Tang, Zorica Janjetovic, Tae-Kang Kim, Zhongzhi Wu, Duane D Miller, Andrzej T Slominski, Arnold E Postlethwaite, Robert C Tuckey, Natacha Rochel, Wei Li
1α,20S-Dihydroxyvitamin D3 [1,20S(OH)2D3], a natural and bioactive vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1α-OH configuration. 1,20S(OH)2D3 interacts with the vitamin D receptor (VDR), with similar potency to its native ligand, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as illustrated by its ability to stimulate translocation of the VDR to the nucleus, stimulate VDRE-reporter activity, regulate VDR downstream genes (VDR, CYP24A1, TRPV6 and CYP27B1), and inhibit the production of inflammatory markers (IFNγ and IL1β)...
August 31, 2017: Scientific Reports
Irfan V Düzen, Fethi Yavuz, Ertan Vuruskan, Erhan Saracoglu, Fatih Poyraz, Hüseyin Göksülük, Basar Candemir, Seniz Demiryürek
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is a major cause of morbidity and mortality. The upregulation of TRP channels is believed to mediate the progression of electrical remodelling and the arrhythmogenesis of the diseased heart. However, there is limited data about the contribution of the TRP channels to development of AF. The aim of this study was to investigate leukocyte TRP channels gene expressions in non-valvular atrial fibrillation (NVAF) patients. The study included 47 NVAF patients and 47 sex and age matched controls...
August 24, 2017: Scientific Reports
Hyun Yang, Changhwan Ahn, Eun-Kyeong Shin, Ji-Sun Lee, Beum-Soo An, Eui-Bae Jeung
Gene knockout is the most powerful tool for determination of gene function or permanent modification of the phenotypic characteristics of an animal. Existing methods for gene disruption are limited by their efficiency, time required for completion and potential for confounding off-target effects. In this study, a rapid single-step approach to knockout of a targeted gene in mice using zinc-finger nucleases (ZFNs) was demonstrated for generation of mutant (knockout; KO) alleles. Specifically, ZFNs to target the sodium/calcium/potassium exchanger3 (NCKX3) gene in C57bl/6j were designed using the concept of this approach...
October 15, 2017: Molecular and Cellular Endocrinology
Ba Hung Do, Hiroki Koizumi, Toyoaki Ohbuchi, Rintaro Kawaguchi, Hideaki Suzuki
OBJECTIVE: We have recently proposed a hypothesis that acid leakage through the cholesteatoma epithelium mediates bone resorption in middle ear cholesteatoma. In the present study, we investigated the expressions of transient receptor potential vanilloid (TRPV) channels, which have been shown to play roles in the regulation of epidermal barrier function, in the cholesteatoma epithelium in comparison with the normal skin. METHODS: Cholesteatoma epithelium and postauricular skin were collected from 17 patients with primary acquired middle ear cholesteatoma who underwent tympanomastoidectomy...
June 9, 2017: Acta Oto-laryngologica
Michiyasu Ishizawa, Daisuke Akagi, Jumpei Yamamoto, Makoto Makishima
The active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ], acts as a ligand for the vitamin D receptor (VDR), and regulates various physiological processes, including calcium and bone metabolism, cellular growth and differentiation, immunity and cardiovascular function. A number of vitamin D derivatives have been synthesized for the treatment of cancer and inflammatory disease, but the adverse effect of hypercalcemic activity due to intestinal calcium absorption has limited wide clinical application...
September 2017: Journal of Steroid Biochemistry and Molecular Biology
Megan R Beggs, Ida Appel, Per Svenningsen, Karsten Skjødt, R Todd Alexander, Henrik Dimke
Significant alterations in maternal calcium (Ca(2+)) and magnesium (Mg(2+)) balance occur during lactation. Ca(2+) is the primary divalent cation mobilized into breast milk by demineralization of the skeleton and alterations in intestinal and renal Ca(2+) transport. Mg(2+) is also concentrated in breast milk, but the underlying mechanisms are not well understood. To determine the molecular alterations in Ca(2+) and Mg(2+) transport in the intestine and kidney during lactation, three groups of female mice consisting of either nonpregnant controls, lactating mice, or mice undergoing involution were examined...
September 1, 2017: American Journal of Physiology. Renal Physiology
Claudia Fecher-Trost, Ulrich Wissenbach, Petra Weissgerber
No abstract text is available yet for this article.
November 2017: Cell Calcium
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