Bioivt Transporter Catalog DG V3
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Viewed Under 23 (B) Or 203 (C) fi M M Male Cko Mice, and Largely Unaffected Magni Cation; Scale Bars, 500 M (B) and 50 M (C)
BRIEF COMMUNICATION www.jasn.org Renal Fanconi Syndrome and Hypophosphatemic Rickets in the Absence of Xenotropic and Polytropic Retroviral Receptor in the Nephron Camille Ansermet,* Matthias B. Moor,* Gabriel Centeno,* Muriel Auberson,* † † ‡ Dorothy Zhang Hu, Roland Baron, Svetlana Nikolaeva,* Barbara Haenzi,* | Natalya Katanaeva,* Ivan Gautschi,* Vladimir Katanaev,*§ Samuel Rotman, Robert Koesters,¶ †† Laurent Schild,* Sylvain Pradervand,** Olivier Bonny,* and Dmitri Firsov* BRIEF COMMUNICATION *Department of Pharmacology and Toxicology and **Genomic Technologies Facility, University of Lausanne, Lausanne, Switzerland; †Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts; ‡Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia; §School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia; |Services of Pathology and ††Nephrology, Department of Medicine, University Hospital of Lausanne, Lausanne, Switzerland; and ¶Université Pierre et Marie Curie, Paris, France ABSTRACT Tight control of extracellular and intracellular inorganic phosphate (Pi) levels is crit- leaves.4 Most recently, Legati et al. have ical to most biochemical and physiologic processes. Urinary Pi is freely filtered at the shown an association between genetic kidney glomerulus and is reabsorbed in the renal tubule by the action of the apical polymorphisms in Xpr1 and primary fa- sodium-dependent phosphate transporters, NaPi-IIa/NaPi-IIc/Pit2. However, the milial brain calcification disorder.5 How- molecular identity of the protein(s) participating in the basolateral Pi efflux remains ever, the role of XPR1 in the maintenance unknown. Evidence has suggested that xenotropic and polytropic retroviral recep- of Pi homeostasis remains unknown. Here, tor 1 (XPR1) might be involved in this process. Here, we show that conditional in- we addressed this issue in mice deficient for activation of Xpr1 in the renal tubule in mice resulted in impaired renal Pi Xpr1 in the nephron. -
Trafficking to the Cell Surface of Amino Acid Transporter SLC6A14
cells Article Trafficking to the Cell Surface of Amino Acid Transporter SLC6A14 Upregulated in Cancer Is Controlled by Phosphorylation of SEC24C Protein by AKT Kinase Vasylyna Kovalchuk and Katarzyna A. Nał˛ecz* Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, PL-02-093 Warsaw, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-225892303 Abstract: Cancer cells need a constant supply of nutrients. SLC6A14, an amino acid transporter B0,+ (ATB0,+) that is upregulated in many cancers, transports all but acidic amino acids. In its exit from the endoplasmic reticulum (ER), it is recognized by the SEC24C subunit of coatomer II (COPII) for further vesicular trafficking to the plasma membrane. SEC24C has previously been shown to be phosphorylated by protein kinase B/AKT, which is hyper-activated in cancer; therefore, we analyzed the influence of AKT on SLC6A14 trafficking to the cell surface. Studies on overexpressed and en- dogenous transporters in the breast cancer cell line MCF-7 showed that AKT inhibition with MK-2206 correlated with a transient increase of the transporter in the plasma membrane, not resulting from the inhibition of ER-associated protein degradation. Two-dimensional electrophoresis demonstrated the decreased phosphorylation of SLC6A14 and SEC24C upon AKT inhibition. A proximity ligation assay confirmed this conclusion: AKT inhibition is correlated with decreased SLC6A14 phosphothreonine Citation: Kovalchuk, V.; Nał˛ecz,K.A. Trafficking to the Cell Surface of and SEC24C phosphoserine. Augmented levels of SLC6A14 in plasma membrane led to increased Amino Acid Transporter SLC6A14 leucine transport. These results show that the inactivation of AKT can rescue amino acid delivery Upregulated in Cancer Is Controlled through SLC6A14 trafficking to the cell surface, supporting cancer cell survival. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Mouse Slc22a2 Knockout Project (CRISPR/Cas9)
https://www.alphaknockout.com Mouse Slc22a2 Knockout Project (CRISPR/Cas9) Objective: To create a Slc22a2 knockout Mouse model (C57BL/6N) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Slc22a2 gene (NCBI Reference Sequence: NM_013667 ; Ensembl: ENSMUSG00000040966 ) is located on Mouse chromosome 17. 11 exons are identified, with the ATG start codon in exon 1 and the TAA stop codon in exon 11 (Transcript: ENSMUST00000046959). Exon 2 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Mice homozygous for a knockout allele are viable and fertile and display no obvious phenotypic abnormalities. No significant defects in the renal secretion of a model organic cation are observed. Exon 2 starts from about 25.02% of the coding region. Exon 2 covers 6.27% of the coding region. The size of effective KO region: ~104 bp. The KO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele 5' gRNA region gRNA region 3' 1 2 11 Legends Exon of mouse Slc22a2 Knockout region Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section upstream of Exon 2 is aligned with itself to determine if there are tandem repeats. Tandem repeats are found in the dot plot matrix. The gRNA site is selected outside of these tandem repeats. -
Transport of Sugars
BI84CH32-Frommer ARI 29 April 2015 12:34 Transport of Sugars Li-Qing Chen,1,∗ Lily S. Cheung,1,∗ Liang Feng,3 Widmar Tanner,2 and Wolf B. Frommer1 1Department of Plant Biology, Carnegie Institution for Science, Stanford, California 94305; email: [email protected] 2Zellbiologie und Pflanzenbiochemie, Universitat¨ Regensburg, 93040 Regensburg, Germany 3Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305 Annu. Rev. Biochem. 2015. 84:865–94 Keywords First published online as a Review in Advance on glucose, sucrose, carrier, GLUT, SGLT, SWEET March 5, 2015 The Annual Review of Biochemistry is online at Abstract biochem.annualreviews.org Soluble sugars serve five main purposes in multicellular organisms: as sources This article’s doi: of carbon skeletons, osmolytes, signals, and transient energy storage and as 10.1146/annurev-biochem-060614-033904 transport molecules. Most sugars are derived from photosynthetic organ- Copyright c 2015 by Annual Reviews. isms, particularly plants. In multicellular organisms, some cells specialize All rights reserved in providing sugars to other cells (e.g., intestinal and liver cells in animals, ∗ These authors contributed equally to this review. photosynthetic cells in plants), whereas others depend completely on an ex- Annu. Rev. Biochem. 2015.84:865-894. Downloaded from www.annualreviews.org ternal supply (e.g., brain cells, roots and seeds). This cellular exchange of Access provided by b-on: Universidade de Lisboa (UL) on 09/05/16. For personal use only. sugars requires transport proteins to mediate uptake or release from cells or subcellular compartments. Thus, not surprisingly, sugar transport is criti- cal for plants, animals, and humans. -
Compositions and Methods for Selective Delivery of Oligonucleotide Molecules to Specific Neuron Types
(19) TZZ ¥Z_T (11) EP 2 380 595 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 26.10.2011 Bulletin 2011/43 A61K 47/48 (2006.01) C12N 15/11 (2006.01) A61P 25/00 (2006.01) A61K 49/00 (2006.01) (2006.01) (21) Application number: 10382087.4 A61K 51/00 (22) Date of filing: 19.04.2010 (84) Designated Contracting States: • Alvarado Urbina, Gabriel AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Nepean Ontario K2G 4Z1 (CA) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL • Bortolozzi Biassoni, Analia Alejandra PT RO SE SI SK SM TR E-08036, Barcelona (ES) Designated Extension States: • Artigas Perez, Francesc AL BA ME RS E-08036, Barcelona (ES) • Vila Bover, Miquel (71) Applicant: Nlife Therapeutics S.L. 15006 La Coruna (ES) E-08035, Barcelona (ES) (72) Inventors: (74) Representative: ABG Patentes, S.L. • Montefeltro, Andrés Pablo Avenida de Burgos 16D E-08014, Barcelon (ES) Edificio Euromor 28036 Madrid (ES) (54) Compositions and methods for selective delivery of oligonucleotide molecules to specific neuron types (57) The invention provides a conjugate comprising nucleuc acid toi cell of interests and thus, for the treat- (i) a nucleic acid which is complementary to a target nu- ment of diseases which require a down-regulation of the cleic acid sequence and which expression prevents or protein encoded by the target nucleic acid as well as for reduces expression of the target nucleic acid and (ii) a the delivery of contrast agents to the cells for diagnostic selectivity agent which is capable of binding with high purposes. -
Interplay Between Metformin and Serotonin Transport in the Gastrointestinal Tract: a Novel Mechanism for the Intestinal Absorption and Adverse Effects of Metformin
INTERPLAY BETWEEN METFORMIN AND SEROTONIN TRANSPORT IN THE GASTROINTESTINAL TRACT: A NOVEL MECHANISM FOR THE INTESTINAL ABSORPTION AND ADVERSE EFFECTS OF METFORMIN Tianxiang Han A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Eshelman School of Pharmacy. Chapel Hill 2013 Approved By: Dhiren R. Thakker, Ph.D. Michael Jay, Ph.D. Kim L. R. Brouwer, Pharm.D., Ph.D. Joseph W. Polli, Ph.D. Xiao Xiao, Ph.D. © 2013 Tianxiang Han ALL RIGHTS RESERVED ii ABSTRACT TIANXIANG HAN: Interplay between Metformin and Serotonin Transport in the Gastrointestinal Tract: A Novel Mechanism for the Intestinal Absorption and Adverse Effects of Metformin (Under the direction of Dhiren R. Thakker, Ph.D.) Metformin is a widely prescribed drug for Type II diabetes mellitus. Previous studies have shown that this highly hydrophilic and charged compound traverses predominantly paracellularly across the Caco-2 cell monolayer, a well-established model for human intestinal epithelium. However, oral bioavailability of metformin is significantly higher than that of the paracellular probe, mannitol (~60% vs ~16%). Based on these observations, the Thakker laboratory proposed a “sponge” hypothesis (Proctor et al., 2008) which states that the functional synergy between apical (AP) transporters and paracellular transport enhances the intestinal absorption of metformin. This dissertation work aims to identify AP uptake transporters of metformin, determine their polarized localization, and elucidate their roles in the intestinal absorption and adverse effects of metformin. Chemical inhibition and transporter-knockdown studies revealed that four transporters, namely, organic cation transporter 1 (OCT1), plasma membrane monoamine transporter (PMAT), serotonin reuptake transporter (SERT) and choline high-affinity transporter (CHT) contribute to AP uptake of metformin in Caco-2 cells. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Correlation Between Apparent Substrate Affinity and OCT2 Transport Turnover S
Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2017/06/14/jpet.117.242552.DC1 1521-0103/362/3/405–412$25.00 https://doi.org/10.1124/jpet.117.242552 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 362:405–412, September 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics Correlation between Apparent Substrate Affinity and OCT2 Transport Turnover s Alyscia Cory Severance, Philip J. Sandoval, and Stephen H. Wright Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona Received April 28, 2017; accepted June 12, 2017 ABSTRACT Organic cation (OC) transporter 2 (OCT2) mediates the first step for six structurally distinct OCT2 substrates and found a strong Downloaded from in the renal secretion of many cationic drugs: basolateral uptake correlation between Jmax and Ktapp; high-affinity substrates from blood into proximal tubule cells. The impact of this process [Ktapp values ,50 mM, including 1-methyl-4-phenylpyridinium, on the pharmacokinetics of drug clearance as estimated using a or 1-methyl-4-phenylpyridinium (MPP), and cimetidine] dis- 22 21 physiologically-based pharmacokinetic approach relies on an played systematically lower Jmax values (,50 pmol cm min ) accurate understanding of the kinetics of transport because the than did low-affinity substrates (Ktapp .200 mM, including choline ratio of the maximal rate of transport to the Michaelis constant and metformin). Similarly, preloading OCT2-expressing cells with (i.e., Jmax/Kt) provides an estimate of the intrinsic clearance (Clint) low-affinity substrates resulted in systematically larger trans- jpet.aspetjournals.org used in in vitro–in vivo extrapolation of experimentally determined stimulated rates of MPP uptake than did preloading with high- transport data. -
Analysis of Dynamic Molecular Networks for Pancreatic Ductal
Pan et al. Cancer Cell Int (2018) 18:214 https://doi.org/10.1186/s12935-018-0718-5 Cancer Cell International PRIMARY RESEARCH Open Access Analysis of dynamic molecular networks for pancreatic ductal adenocarcinoma progression Zongfu Pan1†, Lu Li2†, Qilu Fang1, Yiwen Zhang1, Xiaoping Hu1, Yangyang Qian3 and Ping Huang1* Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors. The rapid progression of PDAC results in an advanced stage of patients when diagnosed. However, the dynamic molecular mechanism underlying PDAC progression remains far from clear. Methods: The microarray GSE62165 containing PDAC staging samples was obtained from Gene Expression Omnibus and the diferentially expressed genes (DEGs) between normal tissue and PDAC of diferent stages were profled using R software, respectively. The software program Short Time-series Expression Miner was applied to cluster, compare, and visualize gene expression diferences between PDAC stages. Then, function annotation and pathway enrichment of DEGs were conducted by Database for Annotation Visualization and Integrated Discovery. Further, the Cytoscape plugin DyNetViewer was applied to construct the dynamic protein–protein interaction networks and to analyze dif- ferent topological variation of nodes and clusters over time. The phosphosite markers of stage-specifc protein kinases were predicted by PhosphoSitePlus database. Moreover, survival analysis of candidate genes and pathways was per- formed by Kaplan–Meier plotter. Finally, candidate genes were validated by immunohistochemistry in PDAC tissues. Results: Compared with normal tissues, the total DEGs number for each PDAC stage were 994 (stage I), 967 (stage IIa), 965 (stage IIb), 1027 (stage III), 925 (stage IV), respectively. The stage-course gene expression analysis showed that 30 distinct expressional models were clustered. -
Analysis of OAT, OCT, OCTN, and Other Family Members Reveals 8
bioRxiv preprint doi: https://doi.org/10.1101/2019.12.23.887299; this version posted December 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Reclassification of SLC22 Transporters: Analysis of OAT, OCT, OCTN, and other Family Members Reveals 8 Functional Subgroups Darcy Engelhart1, Jeffry C. Granados2, Da Shi3, Milton Saier Jr.4, Michael Baker6, Ruben Abagyan3, Sanjay K. Nigam5,6 1Department of Biology, University of California San Diego, La Jolla 92093 2Department of Bioengineering, University of California San Diego, La Jolla 92093 3School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla 92093 4Department of Molecular Biology, Division of Biological Sciences, University of California at San Diego, San Diego, CA, USA 5Department of Pediatrics, University of California San Diego, La Jolla 92093 6Department of Medicine, University of California San Diego, La Jolla 92093 *To whom correspondence should be addressed: [email protected] Running title: Functional subgroups for SLC22 1 bioRxiv preprint doi: https://doi.org/10.1101/2019.12.23.887299; this version posted December 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Among transporters, the SLC22 family is emerging as a central hub of endogenous physiology. -
Disease-Induced Modulation of Drug Transporters at the Blood–Brain Barrier Level
International Journal of Molecular Sciences Review Disease-Induced Modulation of Drug Transporters at the Blood–Brain Barrier Level Sweilem B. Al Rihani 1 , Lucy I. Darakjian 1, Malavika Deodhar 1 , Pamela Dow 1 , Jacques Turgeon 1,2 and Veronique Michaud 1,2,* 1 Tabula Rasa HealthCare, Precision Pharmacotherapy Research and Development Institute, Orlando, FL 32827, USA; [email protected] (S.B.A.R.); [email protected] (L.I.D.); [email protected] (M.D.); [email protected] (P.D.); [email protected] (J.T.) 2 Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada * Correspondence: [email protected]; Tel.: +1-856-938-8697 Abstract: The blood–brain barrier (BBB) is a highly selective and restrictive semipermeable network of cells and blood vessel constituents. All components of the neurovascular unit give to the BBB its crucial and protective function, i.e., to regulate homeostasis in the central nervous system (CNS) by removing substances from the endothelial compartment and supplying the brain with nutrients and other endogenous compounds. Many transporters have been identified that play a role in maintaining BBB integrity and homeostasis. As such, the restrictive nature of the BBB provides an obstacle for drug delivery to the CNS. Nevertheless, according to their physicochemical or pharmacological properties, drugs may reach the CNS by passive diffusion or be subjected to putative influx and/or efflux through BBB membrane transporters, allowing or limiting their distribution to the CNS. Drug transporters functionally expressed on various compartments of the BBB involve numerous proteins from either the ATP-binding cassette (ABC) or the solute carrier (SLC) superfamilies.