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Jian Shi, Francesc Miralles, Lutz Birnbaumer, William A Large, Anthony P Albert
In vascular smooth muscle cells (VSMCs), stimulation of TRPC1-based SOCs mediate Ca(2+) entry pathways which regulate contractility, proliferation and migration. It is therefore important to understand how these channels are activated. Studies have shown that stimulation of TRPC1-based SOCs requires Gαq/PLCβ1 activities and PKC phosphorylation, but it is unclear how store depletion stimulates this gating pathway. The present work examines this issue by focusing on the role of STIM1, an endo/sarcoplasmic reticulum Ca(2+) sensor...
October 18, 2016: Journal of Physiology
Osama Garwain, Suzanne Scarlata
When treated with nerve growth factor (NGF), PC12 cells will differentiate over the course of several days. Here, we have followed changes during differentiation in the cellular levels of phosphoinositide-specific-phospholipase Cβ (PLCβ) and its activator, Gαq, which together mediate Ca(2+) release. We also followed changes in the level of the novel PLCPLCβ binding partner TRAX (translin-associated factor X) which promotes RNA-induced gene silencing. We find that the level of PLCPLCβ increases 4-fold within 24 hrs while Gαq increases only 1...
September 12, 2016: Journal of Biological Chemistry
Mohammed Emehdi Atef, Madhu B Anand-Srivastava
Gqα signaling has been implicated in cardiac hypertrophy. In addition, angiotensin II (Ang II) was also shown to induce its hypertrophic effect through Gqα and PKCδ activation. We recently showed the role of enhanced expression of Gqα/PLCβ1 proteins in vascular smooth muscle cell (VSMC) hypertrophy, however, the role of PKCδ in VSMC hypertrophy in animal model is still lacking. The present study was therefore undertaken to examine the role of PKCδ and the associated signaling mechanisms in VSMC hypertrophy using 16-week-old spontaneously hypertensive rats (SHR)...
2016: PloS One
Stephan Lange, Katja Gehmlich, Alexander S Lun, Jordan Blondelle, Charlotte Hooper, Nancy D Dalton, Erika A Alvarez, Xiaoyu Zhang, Marie-Louise Bang, Yama A Abassi, Cristobal G Dos Remedios, Kirk L Peterson, Ju Chen, Elisabeth Ehler
MLP (muscle LIM protein)-deficient mice count among the first mouse models for dilated cardiomyopathy (DCM), yet the exact role of MLP in cardiac signalling processes is still enigmatic. Elevated PKCα signalling activity is known to be an important contributor to heart failure. Here we show that MLP directly inhibits the activity of PKCα. In end-stage DCM, PKCα is concentrated at the intercalated disc of cardiomyocytes, where it is sequestered by the adaptor protein CARP in a multiprotein complex together with PLCβ1...
2016: Nature Communications
Takehiko Inaba, Takuma Kishimoto, Motohide Murate, Takuya Tajima, Shota Sakai, Mitsuhiro Abe, Asami Makino, Nario Tomishige, Reiko Ishitsuka, Yasuo Ikeda, Shinji Takeoka, Toshihide Kobayashi
Lipid membrane curvature plays important roles in various physiological phenomena. Curvature-regulated dynamic membrane remodeling is achieved by the interaction between lipids and proteins. So far, several membrane sensing/sculpting proteins, such as Bin/amphiphysin/Rvs (BAR) proteins, are reported, but there remains the possibility of the existence of unidentified membrane-deforming proteins that have not been uncovered by sequence homology. To identify new lipid membrane deformation proteins, we applied liposome-based microscopic screening, using unbiased-darkfield microscopy...
July 12, 2016: Proceedings of the National Academy of Sciences of the United States of America
Yuan-Bin Yu, Kuo-Hui Su, Yu Ru Kou, Bei-Chia Guo, Kuan-I Lee, Jeng Wei, Tzong-Shyuan Lee
AIMS: Erythropoietin (EPO), the key hormone involved in erythropoiesis, beneficially affects endothelial cells (ECs), but the detailed mechanisms are yet to be completely understood. In this study, we investigated the role of transient receptor potential vanilloid type 1 (TRPV1), a ligand-gated non-selective calcium (Ca(2+) ) channel, in EPO-mediated endothelial nitric oxide synthase (eNOS) activation and angiogenesis. METHODS AND RESULTS: In ECs, EPO time-dependently increased intracellular levels of calcium; this increase was abrogated by the Ca(2+) chelators and pharmacological inhibitors of TRPV1 in BAECs and TRPV1-transfected HEK293 cells...
May 27, 2016: Acta Physiologica
Omri Matalon, Sophia Fried, Aviad Ben-Shmuel, Maor H Pauker, Noah Joseph, Danielle Keizer, Marina Piterburg, Mira Barda-Saad
Natural killer (NK) cells discriminate between healthy cells and virally infected or transformed self-cells by tuning activating and inhibitory signals received through cell surface receptors. Inhibitory receptors inhibit NK cell function by recruiting and activating the tyrosine phosphatase Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-1 (SHP-1) to the plasma membrane. However, to date, the guanine nucleotide exchange factor VAV1 is the only direct SHP-1 substrate identified in NK cells...
2016: Science Signaling
Susana M Nunes de Miranda, Thomas Wilhelm, Michael Huber, Carolin N Zorn
BACKGROUND: Antigen (Ag)/IgE-mediated mast cell (MC) responses play detrimental roles in allergic diseases. MC activation via the high-affinity receptor for IgE (FcεRI) is controlled by the Src family kinase Lyn. Lyn-deficient (-/-) bone marrow-derived MCs (BMMCs) have been shown by various laboratories to exert stronger activation of the PI3K pathway, degranulation, and production of pro-inflammatory cytokines compared to wild-type (wt) cells. This mimics the phenotype of BMMCs deficient for the SH2-containing inositol-5'-phosphatase 1 (SHIP1)...
2016: Cell Communication and Signaling: CCS
Claudio Raimondi, Veronique Calleja, Riccardo Ferro, Alessandro Fantin, Andrew M Riley, Barry V L Potter, Caroline H Brennan, Tania Maffucci, Banafshé Larijani, Marco Falasca
Strong evidence suggests that phospholipase Cγ1 (PLCγ1) is a suitable target to counteract tumourigenesis and metastasis dissemination. We recently identified a novel signalling pathway required for PLCγ1 activation which involves formation of a protein complex with 3-phosphoinositide-dependent protein kinase 1 (PDK1). In an effort to define novel strategies to inhibit PLCγ1-dependent signals we tested here whether a newly identified and highly specific PDK1 inhibitor, 2-O-benzyl-myo-inositol 1,3,4,5,6-pentakisphosphate (2-O-Bn-InsP5), could affect PDK1/PLCγ1 interaction and impair PLCγ1-dependent cellular functions in cancer cells...
2016: Scientific Reports
Mehran Najibi, Sid Ahmed Labed, Orane Visvikis, Javier Elbio Irazoqui
The mechanisms that tightly control the transcription of host defense genes have not been fully elucidated. We previously identified TFEB as a transcription factor important for host defense, but the mechanisms that regulate TFEB during infection remained unknown. Here, we used C. elegans to discover a pathway that activates TFEB during infection. Gene dkf-1, which encodes a homolog of protein kinase D (PKD), was required for TFEB activation in nematodes infected with Staphylococcus aureus. Conversely, pharmacological activation of PKD was sufficient to activate TFEB...
May 24, 2016: Cell Reports
J Yu, L Zhao, L Liu, F Yang, X Zhu, B Cao
The aim of this study was to confirm the protective effect of tetrahydropalmatine (THP) against irradiation-induced rat pulmonary endothelial cell apoptosis and to explore the underlying mechanism, with a focus on the calcium-sensing receptor (CaSR)/phospholipase C-γ1 (PLC-γ1) pathway. We established a model of irradiation-induced primary rat pulmonary endothelial cell injury. Cell apoptosis and mitochondrial membrane potential (Δψm) were measured by flow cytometry. The expression of CaSR, cytochrome c, PLC-γ1, reactive oxygen species (ROS) and [Ca(2+)]i was also determined...
June 2016: Free Radical Research
Hong Xu, Li-Na Gu, Qian-Yuan Yang, De-Yu Zhao, Feng Liu
Mast cells play a pivotal role in the immediate reaction in asthma. In a previous study, it was found that MicroRNA-221 (miR-221) was associated with asthma. Hence, in the present study, the role and the potential mechanisms of miR-221 on immunoglobulin E (IgE)-mediated activation of mast cells degranulation were investigated. MiR-221 expression was first quantified by qRT-PCR in IgE-mediated activation of mast cells. RBL-2H3 cells were then transfected with miR-221 mimic or miR-221 inhibitor, the IgE-mediated degranulation was detected in mast cells...
June 2016: Journal of Bioenergetics and Biomembranes
Florian A Herzog, Lukas Braun, Ingmar Schoen, Viola Vogel
Specific interactions of protein side chains and lipid membranes regulate the localization, orientation, and activity of many peripheral proteins. Here, we introduce a modification of the coarse-grained MARTINI protein model, called 'side chain fix' (scFix), that was necessary and sufficient to correctly sample the side chain dynamics of β-strands in several globular proteins. When compared to μs long atomistic simulations or previous experimental findings, scFix MARTINI simulations reproduced all key interactions between the well-studied PLC-δ1 pleckstrin homology domain and a phosphatidylinositol-4,5-bisphosphate (PIP2) containing lipid membrane...
May 10, 2016: Journal of Chemical Theory and Computation
Zhai Ertao, Chen Jianhui, Chen Chuangqi, Qin Changjiang, Chen Sile, He Yulong, Wu Hui, Cai Shirong
BACKGROUND: Sonic hedgehog (SHH) plays critical roles in cell growth and development. Tumor cells express SHH, which can promote cell proliferation and epithelial-to-mesenchymal transition. However, the autocrine SHH pathway has not been described in gastric cancer. The aim of this study was to explore molecular mechanisms underlying autocrine SHH signaling in gastric cancer cells. METHODS: SHH expression was assessed using immunohistochemistry and the results were compared with clinicopathologic parameters, including survival...
2016: Journal of Experimental & Clinical Cancer Research: CR
Chloe S Kim, Isaiah P Mitchell, Anthony W Desotell, Pamela K Kreeger, Kristyn S Masters
Epidermal growth factor (EGF) is a critical element in dermal repair, but EGF-containing wound dressings have not been successful clinically. However, these dressings have delivered only soluble EGF, and the native environment provides both soluble and matrix-bound EGF. To address our hypothesis that tethered EGF can stimulate cell behaviors not achievable with soluble EGF, we examined single-cell movement and signaling in human immortalized HaCaT keratinocytes treated with soluble or immobilized EGF. Although both EGF treatments increased collective sheet displacement and individual cell speed, only cells treated with immobilized EGF exhibited directed migration, as well as 2-fold greater persistence compared with soluble EGF...
July 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Laura L Susick, Alexandria C Chrumka, Steven M Hool, Alana C Conti
Brain-derived neurotrophic factor (BDNF) mediates neuron growth and is regulated by adenylyl cyclases (ACs). Mice lacking AC1/8 (DKO) have a basal reduction in the dendritic complexity of medium spiny neurons in the caudate putamen and demonstrate increased neurotoxicity in the striatum following acute neonatal ethanol exposure compared to wild type (WT) controls, suggesting a compromise in BDNF regulation under varying conditions. Although neonatal ethanol exposure can negatively impact BDNF expression, little is known about the effect on BDNF receptor activation and its downstream signaling, including Akt activation, an established neuroprotective pathway...
March 2016: Alcohol
Lei Xiang, Yanping Ren, Xun Li, Wen Zhao, Yijun Song
MicroRNAs (miRs) have been increasingly recognized as post-transcriptional regulators involved in the pathogenesis of epilepsy. Extensive evidence suggests that inhibition of tropomyosin related kinase type B (TrkB) signaling limits epileptogenesis. It has been reported that miR-204 directly targeted and downregulated TrkB protein in a variety of cancers to suppress tumorigenesis, but its effect on epileptogenesis is unknown. Here we showed that miR-204 was downregulated in cultured hippocampal neurons following status epilepticus (SE) induced by Mg(2+)-free treatment...
May 15, 2016: Brain Research
Chengjian Li, Haiou Tong, Qiongxian Yan, Shaoxun Tang, Xuefeng Han, Wenjun Xiao, Zhiliang Tan
BACKGROUND This study aimed to investigate the regulatory effects of L-theanine on secretion of immune cytokines, hormones, and neurotransmitters, and mRNA expression of phospholipase C (PLC) in rats, and to explore its regulatory mechanism in immune function. MATERIAL AND METHODS Sixty-four Sprague-Dawley rats received daily intragastric infusion of different doses of L-theanine solution [0, 50 (LT), 200 (MT), and 400 (HT) mg/kg BW]. Cytokines, immunoglobulins, and hormones in the serum, neurotransmitters, and mRNA expression of PLC in the relevant tissues were assayed...
2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Angela Lanciotti, Maria Stefania Brignone, Sergio Visentin, Chiara De Nuccio, Luigi Catacuzzeno, Cinzia Mallozzi, Stefania Petrini, Martino Caramia, Caterina Veroni, Gaetana Minnone, Antonietta Bernardo, Fabio Franciolini, Mauro Pessia, Enrico Bertini, Tamara Corinna Petrucci, Elena Ambrosini
Mutations in the MLC1 gene, which encodes a protein expressed in brain astrocytes, are the leading cause of MLC, a rare leukodystrophy characterized by macrocephaly, brain edema, subcortical cysts, myelin and astrocyte vacuolation. Although recent studies indicate that MLC1 protein is implicated in the regulation of cell volume changes, the exact role of MLC1 in brain physiology and in the pathogenesis of MLC disease remains to be clarified. In preliminary experiments, we observed that MLC1 was poorly expressed in highly proliferating astrocytoma cells when compared with primary astrocytes, and that modulation of MLC1 expression influenced astrocyte growth...
April 15, 2016: Human Molecular Genetics
Aiko Kume, Koki Kawase, Suguru Komenoi, Takako Usuki, Ena Takeshita, Hiromichi Sakai, Fumio Sakane
Type II diacylglycerol kinase (DGK) isozymes (δ, η, and κ) have a pleckstrin homology domain (PH) at their N termini. Here, we investigated the lipid binding properties of the PHs of type II DGK isozymes using protein-lipid overlay and liposome binding assays. The PH of DGKη showed the most pronounced binding activity to phosphatidylinositol (PI) 4,5-bisphosphate (PI(4,5)P2) among the various glycero- and sphingolipids including PI 3,4,5-trisphosphate, PI 3,4-bisphosphate, PI 3-phosphate, PI 4-phosphate, and PI 5-phosphate...
April 8, 2016: Journal of Biological Chemistry
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