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Functional Insights into the Creatine Transporter

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Creatine and Creatine Kinase in Health and Disease

Part of the book series: Subcellular Biochemistry ((SCBI,volume 46))

Abstract

Creatine and phosphocreatine provide an intracellular, high-energy phosphate buffering system, essential to maintain ATP levels in tissues with high energy demands. A specific plasma membrane creatine transporter (CRT) is required for the cellular uptake of creatine. This transporter is related to the \UPgamma -aminobutyric acid (GAT) and norepinephrine (NET) transporters and is part of a large gene family of Na+- and Cl--dependent neurotransmitter transporters, now known as solute carrier family 6 (SLC6). CRT is essential for normal brain function as mutations in the CRT gene (SLC6A8) result in X-linked mental retardation, associated with the almost complete lack of creatine in the brain, severe speech and language delay, epilepsy, and autistic behaviour. Insight into the structure and function of the CRT has come from studies of creatine transport by tissues and cells, in vitro studies of CRT mutations, identification of mutations associated with CRT deficiency, and from the recent high resolution structure of a prokaryotic homologue of the SLC6 transporters. CRT antibodies have been developed enabling the localization of creatine uptake sites in the brain, retina, muscle and other tissues. These tools in conjunction with the use of appropriate cell models should allow further progress in our knowledge on the regulation and cellular trafficking of the CRT. Development of suitable mouse models may allow improved understanding of the importance of the CRT for normal brain function and how the transporter is regulated in vivo

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References

  • Acosta, M.L., Kalloniatis, M., and Christie, D.L., 2005, Creatine transporter localization in developing and adult retina: importance of creatine to retinal function. Am. J. Physiol. Cell Physiol. 289: C1015–C1023.

    Article  PubMed  CAS  Google Scholar 

  • Alfieri, R.R., Bonelli, M.A., Cavazzoni, A., Briggotti, M., Fumarola, C., Sestili, P., Mozzoni, P., G, D.E.P., Mutti, A., Carnicelli, D., Vacondio, F., Silva, C., Borghetti, A.F., Wheeler, K.P., and Petronini, P.G., 2006, Creatine as a compatible osmolyte in muscle cells exposed to hypertonic stress. J. Physiol. 576: 391–401.

    Article  PubMed  CAS  Google Scholar 

  • Almeida, L.S., Salomons, G.S., Hogenboom, F., Jakobs, C., and Schoffelmeer, A.N., 2006, Exocytotic release of creatine in rat brain. Synapse 60: 118–123.

    Article  PubMed  CAS  Google Scholar 

  • Almeida, L.S., Verhoeven, N.M., Roos, B., Valongo, C., Cardoso, M.L., Vilarinho, L., Salomons, G.S., and Jakobs, C., 2004, Creatine and guanidinoacetate: diagnostic markers for inborn errors in creatine biosynthesis and transport. Mol. Genet. Metab. 82: 214–219.

    Article  PubMed  CAS  Google Scholar 

  • Androutsellis-Theotokis, A., Goldberg, N.R., Ueda, K., Beppu, T., Beckman, M.L., Das, S., Javitch, J.A., and Rudnick, G., 2003, Characterization of a functional bacterial homologue of sodium-dependent neurotransmitter transporters. J. Biol. Chem. 278: 12703–12709.

    Article  PubMed  CAS  Google Scholar 

  • Bernstein, E.M., and Quick, M.W., 1999, Regulation of gamma-aminobutyric acid (GABA) transporters by extracellular GABA. J. Biol. Chem. 274: 889–895.

    Article  PubMed  CAS  Google Scholar 

  • Boehm, E., Chan, S., Monfared, M., Wallimann, T., Clarke, K., and Neubauer, S., 2003, Creatine transporter activity and content in the rat heart supplemented by and depleted of creatine. Am. J. Physiol. Endocrinol. Metab. 284: E399–E406.

    PubMed  CAS  Google Scholar 

  • Brault, J.J., Abraham, K.A., and Terjung, R.L., 2003, Muscle creatine uptake and creatine transporter expression in response to creatine supplementation and depletion. J. Appl. Physiol. 94: 2173–2180.

    Article  PubMed  CAS  Google Scholar 

  • Broer, A., Klingel, K., Kowalczuk, S., Rasko, J.E., Cavanaugh, J., and Broer, S., 2004, Molecular cloning of mouse amino acid transport system B0, a neutral amino acid transporter related to Hartnup disorder. J. Biol. Chem. 279: 24467–24476.

    Article  PubMed  CAS  Google Scholar 

  • Broer, S., 2006, The SLC6 orphans are forming a family of amino acid transporters. Neurochem. Int. 48: 559–567.

    PubMed  Google Scholar 

  • Brone, B., and Eggermont, J., 2005, PDZ proteins retain and regulate membrane transporters in polarized epithelial cell membranes. Am. J. Physiol. Cell Physiol. 288: C20–C29.

    PubMed  CAS  Google Scholar 

  • Buckley, K.M., Melikian, H.E., Provoda, C.J., and Waring, M.T., 2000, Regulation of neuronal function by protein trafficking: a role for the endosomal pathway. J. Physiol. 525: 11–19.

    Article  PubMed  CAS  Google Scholar 

  • Burton, L.D., Kippenberger, A.G., Lingen, B., Bruss, M., Bonisch, H., and Christie, D.L., 1998, A variant of the bovine noradrenaline transporter reveals the importance of the C-terminal region for correct targeting to the membrane and functional expression. Biochem. J. 330: 909–914.

    PubMed  CAS  Google Scholar 

  • Cecil, K.M., DeGrauw, T.J., Salomons, G.S., Jakobs, C., Egelhoff, J.C., and Clark, J.F., 2003, Magnetic resonance spectroscopy in a 9-day-old heterozygous female child with creatine transporter deficiency. J. Comput. Assist. Tomogr. 27: 44–47.

    Article  PubMed  Google Scholar 

  • Chen, J.G., and Rudnick, G., 2000, Permeation and gating residues in serotonin transporter. Proc. Natl. Acad. Sci. USA 97: 1044–1049.

    Article  PubMed  CAS  Google Scholar 

  • Chen, J.G., Sachpatzidis, A., and Rudnick, G., 1997, The third transmembrane domain of the serotonin transporter contains residues associated with substrate and cocaine binding. J. Biol. Chem. {\bf 272: 28321–28327.

    Article  Google Scholar 

  • Chen, N.H., Reith, M.E., and Quick, M.W., 2004, Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6. Pflugers Arch. 447: 519–531.

    Article  PubMed  CAS  Google Scholar 

  • Chiu, C.S., Jensen, K., Sokolova, I., Wang, D., Li, M., Deshpande, P., Davidson, N., Mody, I., Quick, M.W., Quake, S.R., and Lester, H.A., 2002, Number, density, and surface/cytoplasmic distribution of GABA transporters at presynaptic structures of knock-in mice carrying GABA transporter subtype 1-green fluorescent protein fusions. J. Neurosci. 22: 10251–10266.

    PubMed  CAS  Google Scholar 

  • Clark, A.J., Rosenberg, E.H., Almeida, L.S., Wood, T.C., Jakobs, C., Stevenson, R.E., Schwartz, C.E., and Salomons, G.S., 2006, X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology. Hum. Genet. 119: 604–610.

    Article  PubMed  CAS  Google Scholar 

  • Dai, W., Vinnakota, S., Qian, X., Kunze, D.L., and Sarkar, H.K., 1999, Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes. Arch. Biochem. Biophys. 361: 75–84.

    Article  PubMed  CAS  Google Scholar 

  • Daly, M.M., and Seifter, S., 1980, Uptake of creatine by cultured cells. Arch. Biochem. Biophys. 203: 317–324.

    Article  PubMed  CAS  Google Scholar 

  • Deken, S.L., Beckman, M.L., Boos, L., and Quick, M.W., 2000, Transport rates of GABA transporters: regulation by the N-terminal domain and syntaxin 1A. Nat. Neurosci. 3: 998–1003.

    Article  PubMed  CAS  Google Scholar 

  • Deken, S.L., Wang, D., and Quick, M.W., 2003, Plasma membrane GABA transporters reside on distinct vesicles and undergo rapid regulated recycling. J. Neurosci. 23: 1563–1568.

    PubMed  CAS  Google Scholar 

  • Derave, W., Straumann, N., Olek, R.A., and Hespel, P., 2006, Electrolysis stimulates creatine transport and transporter cell surface expression in incubated mouse skeletal muscle: potential role of ROS. Am. J. Physiol. Endocrinol. Metab. 291: E1250–E1257.

    Article  PubMed  CAS  Google Scholar 

  • Dodd, J.R., Zheng, T., and Christie, D.L., 1999, Creatine accumulation and exchange by HEK293 cells stably expressing high levels of a creatine transporter. Biochim. Biophys. Acta 1472: 128–136.

    PubMed  CAS  Google Scholar 

  • Dodd, J.R., and Christie, D.L., 2001, Cysteine 144 in the third transmembrane domain of the creatine transporter is located close to a substrate-binding site. J. Biol. Chem. 276: 46983–46988.

    Article  PubMed  CAS  Google Scholar 

  • Dodd, J.R., and Christie, D.L., 2005, Substituted cysteine accessibility of the third transmembrane domain of the creatine transporter: defining a transport pathway. J. Biol. Chem. 280: 32649–32654.

    Article  PubMed  CAS  Google Scholar 

  • Dodd, J.R., and Christie, D.L., 2007, Selective amino acid substitutions convert the creatine transporter to a gamma -aminobutyric acid transporter. J. Biol. Chem. 282: 15528–15533.

    Article  PubMed  CAS  Google Scholar 

  • Eichler, E.E., Lu, F., Shen, Y., Antonacci, R., Jurecic, V., Doggett, N.A., Moyzis, R.K., Baldini, A., Gibbs, R.A., and Nelson, D.L., 1996, Duplication of a gene-rich cluster between 16p11.1 and Xq28: a novel pericentromeric-directed mechanism for paralogous genome evolution. Hum. Mol. Genet. 5: 899–912.

    Article  PubMed  CAS  Google Scholar 

  • Fitch, C.D., and Shields, R.P., 1966, Creatine metabolism in skeletal muscle. I. Creatine movement across muscle membranes. J. Biol. Chem. 241: 3611–3614.

    PubMed  CAS  Google Scholar 

  • Fitch, C.D., Shields, R.P., Payne, W.F., and Dacus, J.M., 1968, Creatine metabolism in skeletal muscle. 3. Specificity of the creatine entry process. J. Biol. Chem. 243: 2024–2027.

    PubMed  CAS  Google Scholar 

  • Galli, A., DeFelice, L.J., Duke, B.J., Moore, K.R., and Blakely, R.D., 1995, Sodium-dependent norepinephrine-induced currents in norepinephrine- transporter-transfected HEK-293 cells blocked by cocaine and antidepressants. J. Exp. Biol. 198: 2197–2212.

    PubMed  CAS  Google Scholar 

  • Garcia-Delgado, M., Peral, M.J., Cano, M., Calonge, M.L., and Ilundain, A.A., 2001, Creatine transport in brush-border membrane vesicles isolated from rat kidney cortex. J. Am. Soc. Nephrol. 12: 1819–1825.

    PubMed  CAS  Google Scholar 

  • Gether, U., Andersen, P.H., Larsson, O.M., and Schousboe, A., 2006, Neurotransmitter transporters: molecular function of important drug targets. Trends Pharmacol. Sci. 27: 375–383.

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez, A.M., and Uhl, G.R., 1994, ‘Choline/orphan V8-2-1/creatine transporter’ mRNA is expressed in nervous, renal and gastrointestinal systems. Brain Res. Mol. Brain Res. 23: 266–270.

    Article  PubMed  CAS  Google Scholar 

  • Gregor, P., Nash, S.R., Caron, M.G., Seldin, M.F., and Warren, S.T., 1995, Assignment of the creatine transporter gene (SLC6A8) to human chromosome Xq28 telomeric to G6PD. Genomics 25: 332–333.

    Article  PubMed  CAS  Google Scholar 

  • Guastella, J., Nelson, N., Nelson, H., Czyzyk, L., Keynan, S., Miedel, M.C., Davidson, N., Lester, H.A., and Kanner, B.I., 1990, Cloning and expression of a rat brain GABA transporter. Science 249: 1303–1306.

    Article  PubMed  CAS  Google Scholar 

  • Guerrero-Ontiveros, M.L., and Wallimann, T., 1998, Creatine supplementation in health and disease. Effects of chronic creatine ingestion in vivo: down-regulation of the expression of creatine transporter isoforms in skeletal muscle. Mol. Cell. Biochem. 184: 427–437.

    Article  PubMed  CAS  Google Scholar 

  • Guimbal, C., and Kilimann, M.W., 1993, A Na+-dependent creatine transporter in rabbit brain, muscle, heart, and kidney. cDNA cloning and functional expression. J. Biol. Chem. 268: 8418–8421.

    PubMed  CAS  Google Scholar 

  • Guimbal, C., and Kilimann, M.W., 1994, A creatine transporter cDNA from Torpedo illustrates structure/function relationships in the GABA/noradrenaline transporter family. J. Mol. Biol. 241: 317–324.

    Article  PubMed  CAS  Google Scholar 

  • Hahn, K.A., Salomons, G.S., Tackels-Horne, D., Wood, T.C., Taylor, H.A., Schroer, R.J., Lubs, H.A., Jakobs, C., Olson, R.L., Holden, K.R., Stevenson, R.E., and Schwartz, C.E., 2002, X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28. Am. J. Hum. Genet. 70: 1349–1356.

    Article  PubMed  CAS  Google Scholar 

  • Happe, H.K., and Murrin, L.C., 1995, In situ hybridization analysis of CHOT1, a creatine transporter, in the rat central nervous system. J. Comp. Neurol. 351: 94–103.

    Article  PubMed  CAS  Google Scholar 

  • Hemmer, W., Riesinger, I., Wallimann, T., Eppenberger, H.M., and Quest, A.F., 1993, Brain-type creatine kinase in photoreceptor cell outer segments: role of a phosphocreatine circuit in outer segment energy metabolism and phototransduction. J. Cell. Sci. 106: 671–683.

    PubMed  CAS  Google Scholar 

  • Henry, L.K., Defelice, L.J., and Blakely, R.D., 2006, Getting the message across: a recent transporter structure shows the way. Neuron 49: 791–796.

    Article  PubMed  CAS  Google Scholar 

  • Hiel, H., Happe, H.K., Warr, W.B., and Morley, B.J., 1996, Regional distribution of a creatine transporter in rat auditory brainstem: an in-situ hybridization study. Hear. Res. 98: 29–37.

    Article  PubMed  CAS  Google Scholar 

  • Iyer, G.S., Krahe, R., Goodwin, L.A., Doggett, N.A., Siciliano, M.J., Funanage, V.L., and Proujansky, R., 1996, Identification of a testis-expressed creatine transporter gene at 16p11.2 and confirmation of the X-linked locus to Xq28. Genomics 34: 143–146.

    Article  PubMed  CAS  Google Scholar 

  • Kanner, B.I., 2005, Molecular physiology: intimate contact enables transport. Nature 437: 203–205.

    Article  PubMed  CAS  Google Scholar 

  • Lang, F., Henke, G., Embark, H.M., Waldegger, S., Palmada, M., Bohmer, C., and Vallon, V., 2003, Regulation of channels by the serum and glucocorticoid-inducible kinase - implications for transport, excitability and cell proliferation. Cell. Physiol. Biochem. 13: 41–50.

    Article  PubMed  CAS  Google Scholar 

  • Law, R.M., Stafford, A., and Quick, M.W., 2000, Functional regulation of gamma-aminobutyric acid transporters by direct tyrosine phosphorylation. J. Biol. Chem. 275: 23986–23991.

    Article  PubMed  CAS  Google Scholar 

  • Lenz, H., Schmidt, M., Welge, V., Schlattner, U., Wallimann, T., Elsasser, H.P., Wittern, K.P., Wenck, H., Stab, F., and Blatt, T., 2005, The creatine kinase system in human skin: protective effects of creatine against oxidative and UV damage in vitro and in vivo. J. Invest. Dermatol. 124: 443–452.

    Article  PubMed  CAS  Google Scholar 

  • Loder, M.K., and Melikian, H.E., 2003, The dopamine transporter constitutively internalizes and recycles in a protein kinase C-regulated manner in stably transfected PC12 cell lines. J. Biol. Chem. 278: 22168–22174.

    Article  PubMed  CAS  Google Scholar 

  • Loike, J.D., Somes, M., and Silverstein, S.C., 1986, Creatine uptake, metabolism, and efflux in human monocytes and macrophages. Am. J. Physiol. 251: C128–C135.

    PubMed  CAS  Google Scholar 

  • Loike, J.D., Zalutsky, D.L., Kaback, E., Miranda, A.F., and Silverstein, S.C., 1988, Extracellular creatine regulates creatine transport in rat and human muscle cells. Proc. Natl. Acad. Sci. USA 85: 807–811.

    Article  PubMed  CAS  Google Scholar 

  • Loland, C.J., Norregaard, L., and Gether, U., 1999, Defining proximity relationships in the tertiary structure of the dopamine transporter. Identification of a conserved glutamic acid as a third coordinate in the endogenous Zn2+-binding site. J. Biol. Chem. 274: 36928–36934.

    Article  PubMed  CAS  Google Scholar 

  • Lunardi, G., Parodi, A., Perasso, L., Pohvozcheva, A.V., Scarrone, S., Adriano, E., Florio, T., Gandolfo, C., Cupello, A., Burov, S.V., and Balestrino, M., 2006, The creatine transporter mediates the uptake of creatine by brain tissue, but not the uptake of two creatine-derived compounds. Neuroscience 142: 991–997.

    Article  PubMed  CAS  Google Scholar 

  • MacAulay, N., Bendahan, A., Loland, C.J., Zeuthen, T., Kanner, B.I., and Gether, U., 2001, Engineered Zn2 + switches in the gamma-aminobutyric acid (GABA) transporter-1. Differential effects on GABA uptake and currents. J. Biol. Chem. 276: 40476–40485.

    Article  PubMed  CAS  Google Scholar 

  • Mahon, M.J., Donowitz, M., Yun, C.C., and Segre, G.V., 2002, Na+/H+ exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. Nature 417: 858–861.

    Article  PubMed  CAS  Google Scholar 

  • Marescau, B., De Deyn, P., Wiechert, P., Van Gorp, L., and Lowenthal, A., 1986, Comparative study of guanidino compounds in serum and brain of mouse, rat, rabbit, and man. J. Neurochem. 46: 717–720.

    Article  PubMed  CAS  Google Scholar 

  • Mayser, W., Schloss, P., and Betz, H., 1992, Primary structure and functional expression of a choline transporter expressed in the rat nervous system. FEBS Lett. 305: 31–36.

    Article  PubMed  CAS  Google Scholar 

  • Melikian, H.E., 2004, Neurotransmitter transporter trafficking: endocytosis, recycling, and regulation. Pharmacol. Ther. 104: 17–27.

    Article  PubMed  CAS  Google Scholar 

  • Mitchell, S.M., Lee, E., Garcia, M.L., and Stephan, M.M., 2004, Structure and function of extracellular loop 4 of the serotonin transporter as revealed by cysteine-scanning mutagenesis. J. Biol. Chem. 279: 24089–24099.

    Article  PubMed  CAS  Google Scholar 

  • Moller, A., and Hamprecht, B., 1989, Creatine transport in cultured cells of rat and mouse brain. J. Neurochem. 52: 544–550.

    Article  PubMed  CAS  Google Scholar 

  • Murphy, R., McConell, G., Cameron-Smith, D., Watt, K., Ackland, L., Walzel, B., Wallimann, T., and Snow, R., 2001, Creatine transporter protein content, localization, and gene expression in rat skeletal muscle. Am. J. Physiol. Cell Physiol. 280: C415–C422.

    PubMed  CAS  Google Scholar 

  • Nakashima, T., Tomi, M., Katayama, K., Tachikawa, M., Watanabe, M., Terasaki, T., and Hosoya, K., 2004, Blood-to-retina transport of creatine via creatine transporter (CRT) at the rat inner blood-retinal barrier. J. Neurochem. 89: 1454–1461.

    Article  PubMed  CAS  Google Scholar 

  • Nash, S.R., Giros, B., Kingsmore, S.F., Rochelle, J.M., Suter, S.T., Gregor, P., Seldin, M.F., and Caron, M.G., 1994, Cloning, pharmacological characterization, and genomic localization of the human creatine transporter. Receptors Channels 2: 165–174.

    PubMed  CAS  Google Scholar 

  • Nelson, N., 1998, The family of Na+/Cl- neurotransmitter transporters. J. Neurochem. 71: 1785–1803.

    Article  PubMed  CAS  Google Scholar 

  • Norregaard, L., Loland, C.J., and Gether, U., 2003, Evidence for distinct sodium-, dopamine-, and cocaine-dependent conformational changes in transmembrane segments 7 and 8 of the dopamine transporter. J. Biol. Chem. 278: 30587–30596.

    Article  PubMed  CAS  Google Scholar 

  • Odoom, J.E., Kemp, G.J., and Radda, G.K., 1996, The regulation of total creatine content in a myoblast cell line. Mol. Cell. Biochem. 158: 179–188.

    Article  PubMed  CAS  Google Scholar 

  • Ohtsuki, S., Tachikawa, M., Takanaga, H., Shimizu, H., Watanabe, M., Hosoya, K., and Terasaki, T., 2002, The blood-brain barrier creatine transporter is a major pathway for supplying creatine to the brain. J. Cereb. Blood Flow Metab. 22: 1327–1335.

    Article  PubMed  CAS  Google Scholar 

  • Omerovic, E., Bollano, E., Lorentzon, M., Walser, M., Mattsson-Hulten, L., and Isgaard, J., 2003, Growth hormone induces myocardial expression of creatine transporter and decreases plasma levels of IL-1beta in rats during early postinfarct cardiac remodeling. Growth Horm. IGF Res. 13: 239–245.

    Article  PubMed  CAS  Google Scholar 

  • Orsenigo, M.N., Faelli, A., De Biasi, S., Sironi, C., Laforenza, U., Paulmichl, M., and Tosco, M., 2005, Jejunal creatine absorption: what is the role of the basolateral membrane? J. Membr. Biol. 207: 183–195.

    Article  PubMed  CAS  Google Scholar 

  • Paczkowski, F.A., Bryan-Lluka, L.J., Porzgen, P., Bruss, M., and Bonisch, H., 1999, Comparison of the pharmacological properties of cloned rat, human, and bovine norepinephrine transporters. J. Pharmacol. Exp. Ther. 290: 761–767.

    PubMed  CAS  Google Scholar 

  • Peral, M.J., Garcia-Delgado, M., Calonge, M.L., Duran, J.M., De La Horra, M.C., Wallimann, T., Speer, O., and Ilundain, A., 2002, Human, rat and chicken small intestinal Na+-Cl--creatine transporter: functional, molecular characterization and localization. J. Physiol. 545: 133–144.

    Article  PubMed  CAS  Google Scholar 

  • Quick, M., Yano, H., Goldberg, N.R., Duan, L., Beuming, T., Shi, L., Weinstein, H., and Javitch, J.A., 2006, State-dependent conformations of the translocation pathway in the tyrosine transporter Tyt1, a novel neurotransmitter: sodium symporter from Fusobacterium nucleatum. J. Biol. Chem. 281: 26444–26454.

    Article  CAS  Google Scholar 

  • Rosenberg, E.H., Almeida, L.S., Kleefstra, T., deGrauw, R.S., Yntema, H.G., Bahi, N., Moraine, C., Ropers, H.H., Fryns, J.P., deGrauw, T.J., Jakobs, C., and Salomons, G.S., 2004, High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am. J. Hum. Genet. 75: 97–105.

    Article  PubMed  CAS  Google Scholar 

  • Saier, M.H., Jr., 1999, A functional-phylogenetic system for the classification of transport proteins. J. Cell. Biochem. Suppl. 32–33: 84–94.

    Article  PubMed  Google Scholar 

  • Salomons, G.S., van Dooren, S.J., Verhoeven, N.M., Cecil, K.M., Ball, W.S., Degrauw, T.J., and Jakobs, C., 2001, X-linked creatine-transporter gene (SLC6A8) defect: a new creatine- deficiency syndrome. Am. J. Hum. Genet. 68: 1497–1500.

    Article  PubMed  CAS  Google Scholar 

  • Salomons, G.S., van Dooren, S.J., Verhoeven, N.M., Marsden, D., Schwartz, C., Cecil, K.M., DeGrauw, T.J., and Jakobs, C., 2003, X-linked creatine transporter defect: an overview. J. Inherit. Metab. Dis. 26: 309–318.

    Article  PubMed  CAS  Google Scholar 

  • Saltarelli, M.D., Bauman, A.L., Moore, K.R., Bradley, C.C., and Blakely, R.D., 1996, Expression of the rat brain creatine transporter in situ and in transfected HeLa cells. Dev. Neurosci. 18: 524–534.

    PubMed  CAS  Google Scholar 

  • Sandoval, N., Bauer, D., Brenner, V., Coy, J.F., Drescher, B., Kioschis, P., Korn, B., Nyakatura, G., Poustka, A., Reichwald, K., Rosenthal, A., and Platzer, M., 1996, The genomic organization of a human creatine transporter (CRTR) gene located in Xq28. Genomics 35: 383–385.

    Article  PubMed  CAS  Google Scholar 

  • Schlattner, U., Mockli, N., Speer, O., Werner, S., and Wallimann, T., 2002, Creatine kinase and creatine transporter in normal, wounded, and diseased skin. J. Invest. Dermatol. 118: 416–423.

    Article  PubMed  CAS  Google Scholar 

  • Schloss, P., Mayser, W., and Betz, H., 1994, The putative rat choline transporter CHOT1 transports creatine and is highly expressed in neural and muscle-rich tissues. Biochem. Biophys. Res. Commun. 198: 637–645.

    Article  PubMed  CAS  Google Scholar 

  • Sheng, M., and Sala, C., 2001, PDZ domains and the organization of supramolecular complexes. Annu. Rev. Neurosci. 24: 1–29.

    Article  PubMed  CAS  Google Scholar 

  • Shojaiefard, M., Christie, D.L., and Lang, F., 2005, Stimulation of the creatine transporter SLC6A8 by the protein kinases SGK1 and SGK3. Biochem. Biophys. Res. Commun. 334: 742–746.

    Article  PubMed  CAS  Google Scholar 

  • Shojaiefard, M., Christie, D.L., and Lang, F., 2006, Stimulation of the creatine transporter SLC6A8 by the protein kinase mTOR. Biochem. Biophys. Res. Commun. 341: 945–949.

    Article  PubMed  CAS  Google Scholar 

  • Snow, R.J., and Murphy, R.M., 2001, Creatine and the creatine transporter: a review. Mol. Cell. Biochem. 224: 169–181.

    Article  PubMed  CAS  Google Scholar 

  • Sora, I., Richman, J., Santoro, G., Wei, H., Wang, Y., Vanderah, T., Horvath, R., Nguyen, M., Waite, S., Roeske, W.R., and et al., 1994, The cloning and expression of a human creatine transporter. Biochem. Biophys. Res. Commun. 204: 419–427.

    Article  PubMed  CAS  Google Scholar 

  • Speer, O., Neukomm, L.J., Murphy, R.M., Zanolla, E., Schlattner, U., Henry, H., Snow, R.J., and Wallimann, T., 2004, Creatine transporters: a reappraisal. Mol. Cell. Biochem. 256–257: 407–424.

    Article  PubMed  Google Scholar 

  • Stockler, S., Schutz, P.W., and Salomons, G.S., 2007, Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology. Subcell. Biochem. 46: 149–166.

    PubMed  Google Scholar 

  • Straumann, N., Wind, A., Leuenberger, T., and Wallimann, T., 2006, Effects of N-linked glycosylation on the creatine transporter. Biochem. J. 393: 459–469.

    Article  PubMed  CAS  Google Scholar 

  • Sung, U., Apparsundaram, S., Galli, A., Kahlig, K.M., Savchenko, V., Schroeter, S., Quick, M.W., and Blakely, R.D., 2003, A regulated interaction of syntaxin 1A with the antidepressant-sensitive norepinephrine transporter establishes catecholamine clearance capacity. J. Neurosci. 23: 1697–1709.

    PubMed  CAS  Google Scholar 

  • Tarnopolsky, M., Parise, G., Fu, M.H., Brose, A., Parshad, A., Speer, O., and Wallimann, T., 2003, Acute and moderate-term creatine monohydrate supplementation does not affect creatine transporter mRNA or protein content in either young or elderly humans. Mol. Cell. Biochem. 244: 159–166.

    Article  PubMed  CAS  Google Scholar 

  • Tarnopolsky, M.A., Parshad, A., Walzel, B., Schlattner, U., and Wallimann, T., 2001, Creatine transporter and mitochondrial creatine kinase protein content in myopathies. Muscle Nerve 24: 682–688.

    Article  PubMed  CAS  Google Scholar 

  • Ten Hove, M., Chan, S., Lygate, C., Monfared, M., Boehm, E., Hulbert, K., Watkins, H., Clarke, K., and Neubauer, S., 2005, Mechanisms of creatine depletion in chronically failing rat heart. J. Mol. Cell. Cardiol. 38: 309–313.

    Article  PubMed  CAS  Google Scholar 

  • Tosco, M., Faelli, A., Sironi, C., Gastaldi, G., and Orsenigo, M.N., 2004, A creatine transporter is operative at the brush border level of the rat jejunal enterocyte. J. Membr. Biol. 202: 85–95.

    Article  PubMed  CAS  Google Scholar 

  • Tran, T.T., Dai, W., and Sarkar, H.K., 2000, Cyclosporin A inhibits creatine uptake by altering surface expression of the creatine transporter. J. Biol. Chem. 275: 35708–35714.

    Article  PubMed  CAS  Google Scholar 

  • Wallis, J., Lygate, C.A., Fischer, A., ten Hove, M., Schneider, J.E., Sebag-Montefiore, L., Dawson, D., Hulbert, K., Zhang, W., Zhang, M.H., Watkins, H., Clarke, K., and Neubauer, S., 2005, Supranormal myocardial creatine and phosphocreatine concentrations lead to cardiac hypertrophy and heart failure: insights from creatine transporter-overexpressing transgenic mice. Circulation 112: 3131–3139.

    Article  PubMed  CAS  Google Scholar 

  • Walzel, B., Speer, O., Boehm, E., Kristiansen, S., Chan, S., Clarke, K., Magyar, J.P., Richter, E.A., and Wallimann, T., 2002, New creatine transporter assay and identification of distinct creatine transporter isoforms in muscle. Am. J. Physiol. Endocrinol. Metab. 283: E390–E401.

    PubMed  CAS  Google Scholar 

  • Wang, W., Jobst, M.A., Bell, B., Zhao, C.R., Shang, L.H., and Jacobs, D.O., 2002, Cr supplementation decreases tyrosine phosphorylation of the CreaT in skeletal muscle during sepsis. Am. J. Physiol. Endocrinol. Metab. 282: E1046–E1054.

    PubMed  CAS  Google Scholar 

  • West, M., Park, D., Dodd, J., Kistler, J., and Christie, D., 2005, Purification and characterization of the creatine transporter expressed at high levels in HEK293 cells. Prot. Expr. Purif. 41: 393–401.

    Article  CAS  Google Scholar 

  • Whitworth, T.L., and Quick, M.W., 2001, Substrate-induced regulation of gamma-aminobutyric acid transporter trafficking requires tyrosine phosphorylation. J. Biol. Chem. 276: 42932–42937.

    Article  PubMed  CAS  Google Scholar 

  • Wyss, M., and Schulze, A., 2002, Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease? Neuroscience 112: 243–260.

    Article  PubMed  CAS  Google Scholar 

  • Xu, W., Liu, L., Gorman, P.A., Sheer, D., and Emson, P.C., 1997, Assignment of the human creatine transporter type 2 (SLC6A10) to chromosome band 16p11.2 by in situ hybridization. Cytogenet. Cell Genet. 76: 19.

    Article  PubMed  CAS  Google Scholar 

  • Yamashita, A., Singh, S.K., Kawate, T., Jin, Y., and Gouaux, E., 2005, Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters. Nature 437: 215–223.

    Article  PubMed  CAS  Google Scholar 

  • Zhao, C.R., Shang, L., Wang, W., and Jacobs, D.O., 2002, Myocellular creatine and creatine transporter serine phosphorylation after starvation. J. Surg. Res. 105: 10–16.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Molecular, Cell and Developmental Biology Section, School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand

    David L. Christie

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  1. David L. Christie
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  1. VU University Medical Center, Amsterdam, The Netherlands

    Gajja S. Salomons

  2. DSM Nutritional Products Ltd, Basel, Switzerland

    Markus Wyss

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Christie, D.L. (2007). Functional Insights into the Creatine Transporter. In: Salomons, G.S., Wyss, M. (eds) Creatine and Creatine Kinase in Health and Disease. Subcellular Biochemistry, vol 46. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-6486-9_6

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  • DOI: https://doi.org/10.1007/978-1-4020-6486-9_6

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