The cataract and glucosuria associated monocarboxylate transporter MCT12 is a new creatine transporter

被引:50
作者
Abplanalp, Jeannette [1 ]
Laczko, Endre [4 ]
Philp, Nancy J. [6 ]
Neidhardt, John [1 ]
Zuercher, Jurian [1 ]
Braun, Philipp [1 ]
Schorderet, Daniel F. [7 ,8 ,10 ]
Munier, Francis L. [9 ]
Verrey, Francois [2 ,3 ]
Berger, Wolfgang [1 ,3 ,5 ]
Camargo, Simone M. R. [2 ,3 ]
Kloeckener-Gruissem, Barbara [1 ,11 ]
机构
[1] Univ Zurich, Inst Med Mol Genet, Zurich, Switzerland
[2] Univ Zurich, Inst Physiol, Zurich, Switzerland
[3] Univ Zurich, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland
[4] Univ Zurich, ETHZ, Funct Genom Ctr Zurich, Zurich, Switzerland
[5] Univ Zurich, ETHZ, Neurosci Ctr Zurich, Zurich, Switzerland
[6] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA
[7] Inst Res Ophthalmol, Sion, Switzerland
[8] Univ Lausanne, Lausanne, Switzerland
[9] Univ Lausanne, Jules Gonin Eye Hosp, Lausanne, Switzerland
[10] Ecole Polytech Fed Lausanne, Fac Life Sci, Lausanne, Switzerland
[11] ETHZ, Dept Biol, Zurich, Switzerland
基金
美国国家卫生研究院;
关键词
MITOCHONDRIAL PERMEABILITY TRANSITION; AMINO-ACID TRANSPORTER; JUVENILE CATARACT; MOLECULAR CHARACTERIZATION; EPITHELIAL-CELLS; GENE SLC6A8; LENS; KINASE; EXPRESSION; KIDNEY;
D O I
10.1093/hmg/ddt175
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Creatine transport has been assigned to creatine transporter 1 (CRT1), encoded by mental retardation associated SLC6A8. Here, we identified a second creatine transporter (CRT2) known as monocarboxylate transporter 12 (MCT12), encoded by the cataract and glucosuria associated gene SLC16A12. A non-synonymous alteration in MCT12 (p.G407S) found in a patient with age-related cataract (ARC) leads to a significant reduction of creatine transport. Furthermore, Slc16a12 knockout (KO) rats have elevated creatine levels in urine. Transport activity and expression characteristics of the two creatine transporters are distinct. CRT2 (MCT12)-mediated uptake of creatine was not sensitive to sodium and chloride ions or creatine biosynthesis precursors, breakdown product creatinine or creatine phosphate. Increasing pH correlated with increased creatine uptake. MichaelisMenten kinetics yielded a V-max of 838.8 pmol/h/oocyte and a K-m of 567.4 m. Relative expression in various human tissues supports the distinct mutation-associated phenotypes of the two transporters. SLC6A8 was predominantly found in brain, heart and muscle, while SLC16A12 was more abundant in kidney and retina. In the lens, the two transcripts were found at comparable levels. We discuss the distinct, but possibly synergistic functions of the two creatine transporters. Our findings infer potential preventive power of creatine supplementation against the most prominent age-related vision impaired condition.
引用
收藏
页码:3218 / 3226
页数:9
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[1]   THE INFLUENCE OF PH ON MEMBRANE CONDUCTANCE AND INTERCELLULAR RESISTANCE IN THE RAT LENS [J].
BASSNETT, S ;
DUNCAN, G .
JOURNAL OF PHYSIOLOGY-LONDON, 1988, 398 :507-521
[2]   On the mechanism of organelle degradation in the vertebrate lens [J].
Bassnett, Steven .
EXPERIMENTAL EYE RESEARCH, 2009, 88 (02) :133-139
[3]   Functional cooperation of epithelial heteromeric amino acid transporters expressed in madin-darby canine kidney cells [J].
Bauch, C ;
Forster, N ;
Loffing-Cueni, D ;
Summa, V ;
Verrey, F .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (02) :1316-1322
[4]   Detection of variants in SLC6A8 and functional analysis of unclassified missense variants [J].
Betsalel, Ofir T. ;
Pop, Ana ;
Rosenberg, Efraim H. ;
Fernandez-Ojeda, Matilde ;
Jakobs, Cornelis ;
Salomons, Gajja S. .
MOLECULAR GENETICS AND METABOLISM, 2012, 105 (04) :596-601
[5]   Characterization of the monocarboxylate transporter 1 expressed in Xenopus laevis oocytes by changes in cytosolic pH [J].
Bröer, S ;
Schneider, HP ;
Bröer, A ;
Rahman, B ;
Hamprecht, B ;
Deitmer, JW .
BIOCHEMICAL JOURNAL, 1998, 333 :167-174
[6]   Juvenile Cataract-Associated Mutation of Solute Carrier SLC16A12 Impairs Trafficking of the Protein to the Plasma Membrane [J].
Castorino, John J. ;
Gallagher-Colombo, Shannon M. ;
Levin, Alex V. ;
FitzGerald, Paul G. ;
Polishook, Jessica ;
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Ostertag, Eric ;
Philp, Nancy J. .
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2011, 52 (09) :6774-6784
[7]   Identification of Novel Tumor Markers in Prostate, Colon and Breast Cancer by Unbiased Methylation Profiling [J].
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Jelinek, Jaroslav ;
Shen, Lanlan ;
Yu, Yinhua ;
Issa, Jean-Pierre J. .
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[8]   Between-group analysis of microarray data [J].
Culhane, AC ;
Perrière, G ;
Considine, EC ;
Cotter, TG ;
Higgins, DG .
BIOINFORMATICS, 2002, 18 (12) :1600-1608
[9]   Homeostasis in the vertebrate lens: mechanisms of solute exchange [J].
Dahm, Ralf ;
van Marle, Jan ;
Quinlan, Roy A. ;
Prescott, Alan R. ;
Vrensen, Gijs F. J. M. .
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, 2011, 366 (1568) :1265-1277
[10]   Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes [J].
Dai, WX ;
Vinnakota, S ;
Qian, XJ ;
Kunze, DL ;
Sarkar, HK .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1999, 361 (01) :75-84