Genomes and Genes
plasma membrane neurotransmitter transport proteins
Summary: A family of neurotransmitter transporter proteins that facilitate NEUROTRANSMITTER reuptake into PRESYNAPTIC TERMINALS. They may play a role in regulating the intensity and duration of neurotransmission.
- Valayannopoulos V, Boddaert N, Chabli A, Barbier V, Desguerre I, Philippe A, et al. Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect. J Inherit Metab Dis. 2012;35:151-7 pubmed publisher..New treatment strategies are required including creatine derivatives transported independently from CTP or using alternative pathways and transporters. ..
- Salomons G, van Dooren S, Verhoeven N, Marsden D, Schwartz C, Cecil K, et al. X-linked creatine transporter defect: an overview. J Inherit Metab Dis. 2003;26:309-18 pubmed..In approximately 50% of the female carriers, learning disabilities of varying degrees have been noted. ..
- Braissant O, Beard E, Torrent C, Henry H. Dissociation of AGAT, GAMT and SLC6A8 in CNS: relevance to creatine deficiency syndromes. Neurobiol Dis. 2010;37:423-33 pubmed publisher..This suggests that in most brain regions, guanidinoacetate is transported from AGAT- to GAMT-expressing cells through SLC6A8 to allow creatine synthesis, thereby explaining creatine deficiency in SLC6A8-deficient CNS. ..
- Soehnge H, Huang X, Becker M, Whitley P, Conover D, Stern M. A neurotransmitter transporter encoded by the Drosophila inebriated gene. Proc Natl Acad Sci U S A. 1996;93:13262-7 pubmed..From this observation comes a unique opportunity to perform a genetic dissection of the regulation of excitability of the Drosophila motor neuron. ..
- Betsalel O, Rosenberg E, Almeida L, Kleefstra T, Schwartz C, Valayannopoulos V, et al. Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database. Eur J Hum Genet. 2011;19:56-63 pubmed publisher..To provide an accessible database, the 109 currently known SLC6A8 variants, including 35 novel ones, are included in a newly developed LOVD DNA variation database. ..
- Huang X, Huang Y, Chinnappan R, Bocchini C, Gustin M, Stern M. The Drosophila inebriated-encoded neurotransmitter/osmolyte transporter: dual roles in the control of neuronal excitability and the osmotic stress response. Genetics. 2002;160:561-9 pubmed..Furthermore, this threshold value increases with the amount of ine activity. These data suggest that ine mutations confer osmotic stress sensitivity by preventing osmolyte accumulation within the Malpighian tubule and hindgut. ..
- Beuming T, Shi L, Javitch J, Weinstein H. A comprehensive structure-based alignment of prokaryotic and eukaryotic neurotransmitter/Na+ symporters (NSS) aids in the use of the LeuT structure to probe NSS structure and function. Mol Pharmacol. 2006;70:1630-42 pubmed
- Zhou Z, Zhen J, Karpowich N, Goetz R, Law C, Reith M, et al. LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science. 2007;317:1390-3 pubmed publisher..Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters...
- Mercimek Mahmutoglu S, Connolly M, Poskitt K, Horvath G, Lowry N, Salomons G, et al. Treatment of intractable epilepsy in a female with SLC6A8 deficiency. Mol Genet Metab. 2010;101:409-12 pubmed publisher..Heterozygous SLC6A8 deficiency is a potentially treatable condition and should be considered in females with intractable epilepsy and developmental delay/intellectual disability. ..
- Singh S, Yamashita A, Gouaux E. Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature. 2007;448:952-6 pubmed publisher..Our results represent a molecular view into noncompetitive inhibition of a sodium-coupled transporter and define principles for the rational design of new inhibitors...
- Wang H, Elferich J, Gouaux E. Structures of LeuT in bicelles define conformation and substrate binding in a membrane-like context. Nat Struct Mol Biol. 2012;19:212-9 pubmed publisher..Furthermore, using crystals grown in bicelles and the substrate leucine or the substrate analog selenomethionine, we find only a single substrate molecule in the primary binding site. ..
- Farmer M, Robbins M, Medhurst A, Campbell D, Ellington K, Duckworth M, et al. Cloning and characterization of human NTT5 and v7-3: two orphan transporters of the Na+/Cl- -dependent neurotransmitter transporter gene family. Genomics. 2000;70:241-52 pubmed..Although the substrates transported by these transporters remain unknown, their specific but widespread distribution suggests that they may mediate distinct and important functions within the brain and the periphery. ..
- Rosenberg E, Almeida L, Kleefstra T, deGrauw R, Yntema H, Bahi N, et al. High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet. 2004;75:97-105 pubmed..M560V). Our data indicate that the frequency of SLC6A8 mutations in the XLMR population is close to that of CGG expansions in FMR1, the gene responsible for fragile-X syndrome. ..
- Alcaide P, Merinero B, Ruiz Sala P, Richard E, Navarrete R, Arias A, et al. Defining the pathogenicity of creatine deficiency syndrome. Hum Mutat. 2011;32:282-91 pubmed publisher..They also suggest that reducing oxidative stress could be helpful in treating CDS. Hum Mutat 32:1-10, 2011. © 2011 Wiley-Liss, Inc. ..
- Huang Y, Stern M. In vivo properties of the Drosophila inebriated-encoded neurotransmitter transporter. J Neurosci. 2002;22:1698-708 pubmed..These data raise the possibility that Ine negatively regulates neuronal sodium channels, and thus that the substrate neurotransmitter of Ine positively regulates sodium channels. ..
- Kristensen A, Andersen J, Jørgensen T, Sørensen L, Eriksen J, Loland C, et al. SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol Rev. 2011;63:585-640 pubmed publisher..This review provides an update of these advances and their implications for the current understanding of the SLC6 NTTs. ..
- Mandel J. Comparative frequency of fragile-X (FMR1) and creatine transporter (SLC6A8) mutations in X-linked mental retardation. Am J Hum Genet. 2004;75:730-1; author reply 731-2 pubmed
- Liu Q, Mandiyan S, Lopez Corcuera B, Nelson H, Nelson N. A rat brain cDNA encoding the neurotransmitter transporter with an unusual structure. FEBS Lett. 1993;315:114-8 pubmed..The transcript of NTT4 was found exclusively in the central nervous system and is more abundant in the cerebellum and the cerebral cortex. ..
- Piscitelli C, Krishnamurthy H, Gouaux E. Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site. Nature. 2010;468:1129-32 pubmed publisher..We conclude that LeuT harbours a single, centrally located, high-affinity substrate-binding site and that transport is well described by a simple, single-substrate kinetic mechanism. ..
- Zaia K, Reimer R. Synaptic Vesicle Protein NTT4/XT1 (SLC6A17) Catalyzes Na+-coupled Neutral Amino Acid Transport. J Biol Chem. 2009;284:8439-48 pubmed publisher..This characterization of NTT4/XT1 offers important insights into neurotransmitter metabolism as well as the mechanistic differences among the structurally related, but functionally divergent, SLC6 proteins. ..
- Wang H, Gouaux E. Substrate binds in the S1 site of the F253A mutant of LeuT, a neurotransmitter sodium symporter homologue. EMBO Rep. 2012;13:861-6 pubmed publisher..These studies, in combination with previous work, are consistent with a mechanism for LeuT that involves a single high-affinity substrate binding site. ..
- Forrest L, Tavoulari S, Zhang Y, Rudnick G, Honig B. Identification of a chloride ion binding site in Na+/Cl -dependent transporters. Proc Natl Acad Sci U S A. 2007;104:12761-6 pubmed..It is close to the Na1 sodium binding site, thus providing an explanation for the coupling of Cl(-) and Na(+) ions during transport. Other implications of the model are also discussed. ..
- Zhao C, Stolzenberg S, Gracia L, Weinstein H, Noskov S, Shi L. Ion-controlled conformational dynamics in the outward-open transition from an occluded state of LeuT. Biophys J. 2012;103:878-88 pubmed..To the best of our knowledge, our findings shed new light on the Na(+)-driven transport cycle and on the symmetry in structural rearrangements for outward- and inward-open transitions...
- Chiu C, Ross L, Cohen B, Lester H, Gill S. The transporter-like protein inebriated mediates hyperosmotic stimuli through intracellular signaling. J Exp Biol. 2000;203:3531-46 pubmed..We propose that stimulation of MasIne releases intracellular Ca(2+) in native tissues, activating Ca(2+)-dependent K(+) channels, and leading to K(+) transport. ..
- Whone A, Kemp K, Sun M, Wilkins A, Scolding N. Human bone marrow mesenchymal stem cells protect catecholaminergic and serotonergic neuronal perikarya and transporter function from oxidative stress by the secretion of glial-derived neurotrophic factor. Brain Res. 2012;1431:86-96 pubmed publisher..Trophic factor release may afford a way by which intravenously infused MSCs can offer protection to all of the dopaminergic, noradrenergic and serotonergic fibre types degenerating widely throughout the brains of patients with PD. ..
- Geldenhuys W, Lockman P, Philip A, McAfee J, Miller B, McCurdy C, et al. Inhibition of choline uptake by N-cyclohexylcholine, a high affinity ligand for the choline transporter at the blood-brain barrier. J Drug Target. 2005;13:259-66 pubmed..Taken together, the results of these in situ and in silico studies provide further evidence or restrictions that occur with binding to this brain drug delivery vector. ..
- Michelson D, Shevell M, Sherr E, Moeschler J, Gropman A, Ashwal S. Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2011;77:1629-35 pubmed publisher..These values should be among the many factors considered in planning the laboratory evaluation of such children. ..
- Perez C, Ziegler C. Mechanistic aspects of sodium-binding sites in LeuT-like fold symporters. Biol Chem. 2013;394:641-8 pubmed publisher..Moreover, we highlight their crucial roles in conformational changes of LeuT-like fold transporters and their implication on a unifying mechanism in secondary transport. ..
- Boenzi S, Pastore A, Martinelli D, Goffredo B, Boiani A, Rizzo C, et al. Creatine metabolism in urea cycle defects. J Inherit Metab Dis. 2012;35:647-53 pubmed publisher..Since arginine in most UCDs becomes a semi-essential aminoacid, measuring plasma Cr concentrations might be of help to optimize the dose of arginine substitution. ..
- Simmons K, Gotfryd K, Billesbølle C, Loland C, Gether U, Fishwick C, et al. A virtual high-throughput screening approach to the discovery of novel inhibitors of the bacterial leucine transporter, LeuT. Mol Membr Biol. 2013;30:184-94 pubmed publisher..This paper describes application of this technique to the discovery of inhibitors of the leucine transporter (LeuT), a member of the neurotransmitter:sodium symporter (NSS) family. ..
- Puusepp H, Käll K, Salomons G, Talvik I, Männamaa M, Rein R, et al. The screening of SLC6A8 deficiency among Estonian families with X-linked mental retardation. J Inherit Metab Dis. 2010;33 Suppl 3:S5-11 pubmed..We therefore conclude that creatine transporter deficiency is a relatively common genetic disorder in males with sporadic or familiar MR and diagnostic screening of them should always include screening for SLC6A8 deficiency. ..
- Wilczynska J, Pfeil U, Zakrzewicz A, Dietrich H, Korner C, Hecker A, et al. Acetylcholine and chronic vasculopathy in rat renal allografts. Transplantation. 2011;91:263-70 pubmed publisher..Treatment with rivastigmine drastically exacerbated CAV compared with placebo. We suggest that endogenous ACh contributes to the pathogenesis of CAV and may be a promising target for novel therapies preventing CAV. ..
- Slotkin T, Ryde I, Seidler F. Additive and synergistic effects of fetal nicotine and dexamethasone exposure on cholinergic synaptic function in adolescence and adulthood: Implications for the adverse consequences of maternal smoking and pharmacotherapy of preterm delivery. Brain Res Bull. 2010;81:552-60 pubmed publisher..Our results thus point to potentially worse neurobehavioral outcomes of the pharmacotherapy of preterm labor in the offspring of smokers...
- Matsumoto K, Shimodaira M, Nakagawa T, Nakayama T, Nakazato T, Izumi Y, et al. Association study: SLC6A18 gene and myocardial infarction. Clin Biochem. 2011;44:789-94 pubmed publisher..037). These results suggest that SLC6A18 or neighboring genes are associated with increased susceptibility to MI. ..
- Betsalel O, van de Kamp J, Martínez Muñoz C, Rosenberg E, de Brouwer A, Pouwels P, et al. Detection of low-level somatic and germline mosaicism by denaturing high-performance liquid chromatography in a EURO-MRX family with SLC6A8 deficiency. Neurogenetics. 2008;9:183-90 pubmed publisher..This study indicates DHPLC as an important tool in the detection of low-level mosaicism, as does it illustrate the importance of considering somatic and germline mosaicism in the case of apparent de novo mutation. ..
- Schiaffino M, Bellini C, Costabello L, Caruso U, Jakobs C, Salomons G, et al. X-linked creatine transporter deficiency: clinical description of a patient with a novel SLC6A8 gene mutation. Neurogenetics. 2005;6:165-8 pubmed
- Tachikawa M, Hosoya K, Ohtsuki S, Terasaki T. A novel relationship between creatine transport at the blood-brain and blood-retinal barriers, creatine biosynthesis, and its use for brain and retinal energy homeostasis. Subcell Biochem. 2007;46:83-98 pubmed
- Schloss P, Mayser W, Betz H. The putative rat choline transporter CHOT1 transports creatine and is highly expressed in neural and muscle-rich tissues. Biochem Biophys Res Commun. 1994;198:637-45 pubmed..High expression was also seen in the rat embryo along the entire neuraxis and in some non-neuronal tissues. These data establish CHOT1 as a widely expressed rat creatine transporter. ..
- Wang H, Goehring A, Wang K, Penmatsa A, Ressler R, Gouaux E. Structural basis for action by diverse antidepressants on biogenic amine transporters. Nature. 2013;503:141-5 pubmed publisher..Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs. ..
- Neira V, Romero Espinoza P, Rojas Martinez A, Ortiz Lopez R, Córdova Fletes C, Plaja A, et al. De novo MECP2 disomy in a Mexican male carrying a supernumerary marker chromosome and no typical Lubs syndrome features. Gene. 2013;524:381-5 pubmed publisher..1Mb. Despite gain of the MECP2 gene, the features of this patient do not evoke Lubs syndrome. Probably the mosaicism of the supernumerary marker chromosome is modifying the phenotype in this patient. ..
- Pramod A, Foster J, Carvelli L, Henry L. SLC6 transporters: structure, function, regulation, disease association and therapeutics. Mol Aspects Med. 2013;34:197-219 pubmed publisher..Recent advances providing structural insight into this family have vastly accelerated our ability to study these proteins and their involvement in complex biological processes. ..
- Zhang Z, Witham S, Petukh M, Moroy G, Miteva M, Ikeguchi Y, et al. A rational free energy-based approach to understanding and targeting disease-causing missense mutations. J Am Med Inform Assoc. 2013;20:643-51 pubmed publisher..This observation is used to demonstrate, computationally and experimentally, that a particular condition, Snyder-Robinson syndrome caused by the G56S spermine synthase mutation, might be ameliorated by small molecule binding. ..
- Lips K, Pfeil U, Haberberger R, Kummer W. Localisation of the high-affinity choline transporter-1 in the rat skeletal motor unit. Cell Tissue Res. 2002;307:275-80 pubmed..This preferential localisation matches well with its anticipated pivotal role in synaptic transmitter recycling and synthesis. ..
- Shojaiefard M, Christie D, Lang F. Stimulation of the creatine transporter SLC6A8 by the protein kinases SGK1 and SGK3. Biochem Biophys Res Commun. 2005;334:742-6 pubmed..Deranged SGK1 and/or SGK3 dependent regulation of SLC6A8 may affect energy storage particularly in skeletal muscle, heart, and neurons. ..
- White J, Juniku R, Huang K, Yang J, Wong D. Synthesis of 1,1-[1-naphthyloxy-2-thiophenyl]-2-methylaminomethylcyclopropanes and their evaluation as inhibitors of serotonin, norepinephrine, and dopamine transporters. J Med Chem. 2009;52:5872-9 pubmed publisher..In vitro assays of the synthesized cyclopropanes revealed that the K(i) of one of the enantiomers as a dual inhibitor of serotonin and norepinephrine transporters is in the low nanomolar range and is comparable to that of duloxetine. ..
- Osaka H, Takagi A, Tsuyusaki Y, Wada T, Iai M, Yamashita S, et al. Contiguous deletion of SLC6A8 and BAP31 in a patient with severe dystonia and sensorineural deafness. Mol Genet Metab. 2012;106:43-7 pubmed publisher..Our case supports the idea that the loss of BAP31 is related to liver dysfunction and hearing loss. ..
- Mencarelli M, Tassini M, Pollazzon M, Vivi A, Calderisi M, Falco M, et al. Creatine transporter defect diagnosed by proton NMR spectroscopy in males with intellectual disability. Am J Med Genet A. 2011;155A:2446-52 pubmed publisher..We conclude that Cr/Crn ratio measured by NMR for male patients represents a rapid and useful first level screening test preceding molecular analysis. ..
- Longo N, Ardon O, Vanzo R, Schwartz E, Pasquali M. Disorders of creatine transport and metabolism. Am J Med Genet C Semin Med Genet. 2011;157C:72-8 pubmed publisher..The excellent response to therapy of early identified patients with GAMT or AGAT deficiency candidates these condition for inclusion in newborn screening programs. ..