Affinage

SLC6A8

Sodium- and chloride-dependent creatine transporter 1 · UniProt P48029

Length
635 aa
Mass
70.5 kDa
Annotated
2026-04-28
100 papers in source corpus 24 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC6A8 is a Na⁺/Cl⁻-dependent creatine transporter that mediates concentrative creatine uptake in brain, muscle, heart, and immune cells, requiring at least two Na⁺ ions and one Cl⁻ ion per creatine molecule with a Km of ~20 µM (PMID:9882430). Its transport activity is positively regulated by SGK1/SGK3 (via PIKfyve phosphorylation at S318) and mTOR, and negatively regulated by SPAK, OSR1, JAK2, and JAK3, while Klotho stabilizes the transporter at the plasma membrane through its β-glucuronidase activity (PMID:16036218, PMID:17982255, PMID:16466692, PMID:25531585, PMID:22407360, PMID:25531216). Loss-of-function mutations in SLC6A8 cause X-linked creatine transporter deficiency, characterized by cerebral creatine depletion and cognitive impairment; in the CNS, SLC6A8 also transports guanidinoacetate between AGAT- and GAMT-expressing cells to support local creatine biosynthesis, and its absence from blood-brain barrier astrocytes limits peripheral creatine import (PMID:11326334, PMID:18392746, PMID:29384270). In macrophages, SLC6A8-mediated creatine uptake reprograms polarization by suppressing IFN-γ–JAK–STAT1 signaling and promoting IL-4–STAT6-driven chromatin remodeling, and in cancer cells, creatine import through SLC6A8 supports bioenergetics and survival under hypoxia (PMID:31399282, PMID:34613776, PMID:33990217).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    Establishing the genomic organization of SLC6A8 at Xq28 provided the structural framework necessary for subsequent mutation screening and disease gene identification.

    Evidence Large-scale genomic sequencing defined 13 exons spanning ~8.5 kb at Xq28

    PMID:8661155

    Open questions at the time
    • No functional data on transport at this stage
    • Regulatory elements not mapped
  2. 1999 High

    Reconstitution of human SLC6A8 in Xenopus oocytes defined the fundamental transport mechanism — Na⁺/Cl⁻-dependent concentrative creatine uptake with ~20 µM affinity — and established the heterologous expression system used in most subsequent regulatory studies.

    Evidence Radiolabeled creatine uptake and ion-substitution kinetics in Xenopus oocytes expressing human SLC6A8

    PMID:9882430

    Open questions at the time
    • Structure of the transporter unknown
    • In vivo relevance not yet demonstrated
  3. 2001 High

    Identification of a hemizygous nonsense mutation in a patient with cerebral creatine deficiency proved that SLC6A8 loss of function is the genetic basis of X-linked creatine transporter deficiency, converting a biochemical activity into a disease gene.

    Evidence Mutation analysis and fibroblast creatine uptake assay in index patient, confirmed by proton MRS

    PMID:11326334

    Open questions at the time
    • Genotype–phenotype correlation across variant classes not established
    • Blood-brain barrier mechanism not yet addressed
  4. 2005 High

    Discovery that SGK1/SGK3 stimulate SLC6A8 maximal transport rate without altering substrate affinity opened the field of kinase-mediated transporter regulation and was subsequently extended to a PIKfyve→SGK1 axis and mTOR signaling.

    Evidence Xenopus oocyte electrophysiology with co-expressed constitutively active SGK isoforms; PIKfyve S318A mutagenesis; rapamycin and dominant-negative SGK1 experiments

    PMID:16036218 PMID:16466692 PMID:17982255

    Open questions at the time
    • Whether these regulatory mechanisms operate in native tissues is untested
    • Direct phosphorylation of SLC6A8 itself not demonstrated
  5. 2007 High

    Systematic functional classification of pathogenic missense variants revealed that loss of creatine uptake can arise from either trafficking failure or substrate-binding-pocket disruption, establishing mechanistic heterogeneity among disease alleles.

    Evidence Site-directed mutagenesis and creatine uptake assay in SLC6A8-deficient fibroblasts for 13 variants

    PMID:17465020

    Open questions at the time
    • No structural model to explain residue-level defects
    • No attempt at pharmacological rescue
  6. 2008 High

    Cell-type mapping in the CNS revealed that SLC6A8 is absent from blood-brain barrier astrocytes and that AGAT and GAMT are expressed in distinct brain cell populations, establishing that SLC6A8 transports guanidinoacetate between cells to enable local creatine synthesis — explaining why SLC6A8 deficiency causes cerebral creatine depletion despite intact synthetic enzymes.

    Evidence Immunohistochemistry/in situ hybridization co-expression mapping and radiolabeled guanidinoacetate uptake in reaggregating brain cell cultures

    PMID:18392746 PMID:19879361

    Open questions at the time
    • Relative contributions of intercellular guanidinoacetate transport vs. direct creatine import not quantified
    • No genetic manipulation of BBB astrocytes
  7. 2011 High

    Ubiquitous Slc6a8 knockout mice confirmed that SLC6A8 is essential for creatine uptake in vivo, with complete brain and muscle creatine loss causing learning/memory deficits and serotonergic neurotransmitter imbalance.

    Evidence Cre-loxP global KO with HPLC creatine measurement, Morris water maze, novel object recognition, conditioned fear, and hippocampal neurotransmitter quantification

    PMID:21249153

    Open questions at the time
    • Contribution of peripheral vs. central creatine loss to cognitive deficits not dissociated
    • Mechanism linking creatine to serotonin metabolism unknown
  8. 2012 High

    JAK2 was identified as a negative regulator that reduces SLC6A8 maximal transport by inhibiting carrier insertion into the plasma membrane (not by accelerating removal), introducing a new regulatory axis distinct from SGK1/mTOR-mediated stimulation.

    Evidence Xenopus oocyte electrophysiology with constitutively active V617F and kinase-dead K882E JAK2; brefeldin A trafficking assay

    PMID:22407360

    Open questions at the time
    • JAK2 regulation not validated in mammalian cells
    • Direct vs. indirect mechanism on SLC6A8 not resolved
  9. 2014 High

    Additional negative regulators SPAK and OSR1 and a positive stabilizer Klotho were identified, expanding the kinase/enzyme network controlling SLC6A8 surface density and maximal transport rate.

    Evidence Xenopus oocyte electrophysiology with constitutively active/kinase-dead SPAK and OSR1 mutants; Klotho co-expression with brefeldin A membrane stability assay and β-glucuronidase inhibitor

    PMID:25531216 PMID:25531585

    Open questions at the time
    • In vivo relevance of Klotho-SLC6A8 axis unconfirmed
    • Mechanism by which β-glucuronidase activity stabilizes SLC6A8 at the membrane is unknown
  10. 2018 High

    Brain-specific Slc6a8 knockout dissociated central from peripheral effects, proving that loss of cerebral creatine alone — independent of muscle/systemic creatine — is sufficient to cause cognitive deficits and hyperactivity.

    Evidence Nestin-Cre conditional KO with tissue creatine/guanidinoacetate measurement and behavioral testing (Morris water maze, novel object recognition, fear conditioning, open field)

    PMID:29384270

    Open questions at the time
    • Cell-type-specific roles in neurons vs. oligodendrocytes not resolved
    • Therapeutic rescue by creatine supplementation not tested in this model
  11. 2019 High

    SLC6A8-mediated creatine uptake was shown to directly reprogram macrophage polarization by inhibiting IFN-γ–JAK–STAT1 signaling and promoting IL-4–STAT6 chromatin remodeling, establishing a non-neuronal, immunometabolic function for SLC6A8.

    Evidence Macrophage-specific Slc6a8 ablation with cytokine stimulation, STAT1/STAT6 signaling, chromatin remodeling assays, and in vivo functional studies

    PMID:31399282

    Open questions at the time
    • Exact metabolic intermediates through which creatine modulates JAK-STAT signaling not identified
    • Role in adaptive immunity beyond macrophages only partially explored
  12. 2020 High

    Quantitative profiling of pathogenic variants established that all tested disease mutations exhibit proteostatic deficiencies (reduced expression or trafficking), while a subset additionally disrupts the substrate-binding pocket — classifying disease mechanisms into trafficking-defective and binding-defective categories and identifying 4-PBA as a potential proteostasis-based corrector.

    Evidence Creatine uptake, cell-surface trafficking quantification, structural homology modeling, temperature sensitivity, and 4-PBA treatment in HEK293T cells

    PMID:32207963

    Open questions at the time
    • 4-PBA efficacy on patient-derived cells not tested
    • No experimental structure to validate homology models
  13. 2021 High

    SLC6A8 emerged as a cancer-relevant transporter: pharmacological inhibition by RGX-202 depleted intracellular phosphocreatine/ATP and suppressed colorectal cancer growth across multiple in vivo models, while in triple-negative breast cancer SLC6A8 was transcriptionally upregulated by NF-κB under hypoxia to promote survival via AKT-ERK signaling.

    Evidence RGX-202 transport inhibition assay, xenograft/syngeneic/PDX models, metabolite measurement; siRNA knockdown in TNBC cells with ROS/OCR measurement and xenograft

    PMID:33990217 PMID:34613776

    Open questions at the time
    • Selectivity of RGX-202 for SLC6A8 over other SLC6 family members not fully characterized
    • Clinical efficacy data pending
  14. 2023 High

    Mass spectrometry interactomics of WT and mutant SLC6A8 revealed that pathogenic variants enrich ER-resident binding partners (consistent with ER retention) and that specific variants disrupt protein–protein interaction interfaces, providing a molecular explanation for variant-specific trafficking failure.

    Evidence Co-immunoprecipitation mass spectrometry in HEK293T, homology modeling of inward/outward-facing conformations, functional assays

    PMID:38070861

    Open questions at the time
    • Interactome not validated by reciprocal pulldown or proximity labeling
    • Cryo-EM or crystal structure of SLC6A8 still lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of SLC6A8 in multiple conformational states, the direct phosphorylation events on SLC6A8 itself (if any) underlying kinase regulation, the molecular basis of guanidinoacetate vs. creatine selectivity, and whether pharmacological chaperones can rescue trafficking-defective variants in patients.
  • No experimental atomic-resolution structure
  • Direct post-translational modification sites on SLC6A8 unmapped
  • Therapeutic rescue strategy for trafficking-defective mutations untested in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1430728 Metabolism 3 R-HSA-382551 Transport of small molecules 3 R-HSA-168256 Immune System 2
Partners
JAK2JAK3MTOROSR1PIKFYVESGK1SGK3SPAK

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 SLC6A8 encodes a creatine transporter whose loss-of-function (hemizygous nonsense mutation) causes cerebral creatine deficiency; fibroblasts from the index patient were defective in creatine uptake, establishing SLC6A8 as the gene responsible for X-linked creatine transporter deficiency syndrome. Fibroblast creatine uptake assay, mutation analysis (nonsense mutation in SLC6A8), proton MRS American journal of human genetics High 11326334
1999 Human SLC6A8 (CRT-1) expressed in Xenopus oocytes mediates Na+- and Cl−-dependent concentrative creatine uptake with Km ~20 µM; transport requires at least two Na+ ions and one Cl− ion per creatine molecule; activity is inhibited by beta-guanidinopropionic acid, cyclocreatine, and amiloride; protein kinase C activation (PMA) inhibits transport while PKA activation does not. Xenopus oocyte expression system, radiolabeled creatine uptake assay, ion-substitution kinetics, pharmacological inhibitors, phorbol ester treatment Archives of biochemistry and biophysics High 9882430
1996 The SLC6A8 (CRTR) gene is located at Xq28, contains 13 exons spanning ~8.5 kb of genomic DNA, approximately 36 kb centromeric to the ALD gene. Large-scale genomic sequencing, gene structure analysis Genomics High 8661155
2005 SLC6A8 creatine transport activity in Xenopus oocytes is stimulated by co-expression of SGK1 (serum- and glucocorticoid-inducible kinase 1) and SGK3, but not by SGK2 or PKB; constitutively active SGK1/SGK3 increase maximal transport rate without altering creatine affinity. Xenopus oocyte expression system, two-electrode voltage-clamp electrophysiology, kinetic analysis Biochemical and biophysical research communications High 16036218
2006 mTOR stimulates SLC6A8 creatine transport activity in Xenopus oocytes, increasing maximal transport rate; this effect is blocked by rapamycin and by inactive SGK1, indicating mTOR acts at least partially through SGK1. Xenopus oocyte expression system, two-electrode voltage-clamp, rapamycin inhibition Biochemical and biophysical research communications High 16466692
2007 PIKfyve (PIP5K3) mediates SGK1-dependent stimulation of SLC6A8 in Xenopus oocytes; SGK1 phosphorylates PIKfyve at its consensus serine (S318), and a S318A-PIKfyve mutant abolishes both PIKfyve- and SGK1-stimulated SLC6A8 activity, establishing PIKfyve as an intermediate in the SGK1→SLC6A8 regulatory axis. Xenopus oocyte co-expression, two-electrode voltage-clamp, site-directed mutagenesis (S318A PIKfyve) Cellular physiology and biochemistry High 17982255
2007 Missense variants in SLC6A8 were functionally classified by site-directed mutagenesis and transient transfection into SLC6A8-deficient fibroblasts; nine variants (p.Gly87Arg, p.Phe107del, p.Tyr317X, p.Asn336del, p.Cys337Trp, p.Ile347del, p.Pro390Leu, p.Arg391Trp, p.Pro554Leu) were proven pathogenic (loss of creatine uptake) and four were nonpathogenic. Site-directed mutagenesis, transient transfection, creatine uptake assay in SLC6A8-deficient fibroblasts Human mutation High 17465020
2012 JAK2 downregulates SLC6A8 creatine transport in Xenopus oocytes; constitutively active (V617F)JAK2 but not kinase-dead (K882E)JAK2 reduces maximal transport rate; JAK2 inhibitor AG490 reverses this suppression; brefeldin A experiments indicate JAK2 does not alter carrier membrane half-life, suggesting interference with carrier insertion into the plasma membrane. Xenopus oocyte expression, two-electrode voltage-clamp, constitutively active and kinase-dead JAK2 mutants, brefeldin A trafficking assay, pharmacological inhibition The Journal of membrane biology High 22407360
2012 Four non-truncating SLC6A8 mutations abolish both electrogenic creatine transport and creatine uptake in Xenopus oocytes and patient fibroblasts; all mutant proteins are properly targeted to the plasma membrane, indicating a functional defect rather than a trafficking defect; guanidinopropionate activates wild-type SLC6A8 electrogenically similar to creatine, while a phosphocreatine derivative (PCr-Mg-CPLX) shows only partial activity. Xenopus oocyte electrophysiology, [14C]-creatine uptake, immunofluorescence, western blot, subcellular localization Journal of inherited metabolic disease High 22644605
2014 SPAK (constitutively active T233E form, requires catalytic activity) and OSR1 (wild-type, T185E, T185A forms, requires catalytic activity) negatively regulate SLC6A8 by decreasing maximal transport rate in Xenopus oocytes. Xenopus oocyte expression, two-electrode voltage-clamp, constitutively active and kinase-dead mutants of SPAK and OSR1 Kidney & blood pressure research High 25531585
2014 Klotho protein upregulates SLC6A8 creatine transporter activity in Xenopus oocytes by stabilizing the carrier in the plasma membrane (assessed by delayed brefeldin A-induced current decline); the effect requires Klotho's β-glucuronidase activity and is reproduced by recombinant soluble Klotho. Xenopus oocyte co-expression, two-electrode voltage-clamp, brefeldin A membrane insertion assay, β-glucuronidase inhibitor (DSAL), recombinant Klotho protein Kidney & blood pressure research High 25531216
2015 JAK3 negatively regulates SLC6A8 creatine transport in Xenopus oocytes; constitutively active A568V JAK3 but not kinase-dead K851A JAK3 decreases maximal creatine transport rate; the JAK3 inhibitor WHI-P154 reverses suppression. Xenopus oocyte expression, two-electrode voltage-clamp, constitutively active and kinase-dead JAK3 mutants, pharmacological inhibition Neuro-Signals High 26666525
2008 In the CNS, SLC6A8 is absent from astrocytes surrounding the blood-brain barrier, limiting creatine import from the periphery; furthermore, AGAT and GAMT are largely expressed in distinct (non-overlapping) brain cell populations, and brain cells take up guanidinoacetate and convert it to creatine via SLC6A8-mediated intercellular transport, explaining why SLC6A8 deficiency causes cerebral creatine deficiency despite intact AGAT and GAMT expression. Immunohistochemistry/in situ hybridization for AGAT, GAMT, SLC6A8 co-expression analysis; reaggregating brain cell cultures with radiolabeled guanidinoacetate uptake and competition assays Journal of inherited metabolic disease / Neurobiology of disease High 18392746 19879361
2011 Ubiquitous Slc6a8 knockout mice lack creatine in brain and muscle and show learning/memory deficits (Morris water maze, novel object recognition, fear conditioning) with increased serotonin and 5-HIAA in hippocampus and prefrontal cortex, establishing SLC6A8 as required for creatine uptake in vivo and linking brain creatine to cognitive function. Cre-loxP knockout mouse (exons 2–4 deleted), HPLC-based creatine measurement, Morris water maze, novel object recognition, conditioned fear, neurotransmitter quantification PloS one High 21249153
2018 Brain-specific Slc6a8 knockout (Nestin-Cre) mice have reduced cerebral creatine with normal peripheral creatine and display cognitive deficits (Morris water maze, novel object recognition, fear conditioning) and hyperactivity; brain guanidinoacetate (creatine synthesis precursor) is increased, confirming SLC6A8 is required for cerebral creatine homeostasis and that loss of brain creatine alone is sufficient to cause the cognitive phenotype. Nestin-Cre conditional KO, creatine/guanidinoacetate tissue measurement, Morris water maze, novel object recognition, fear conditioning, open field Genes, brain, and behavior High 29384270
2014 SLC6A8 knockout mouse skeletal muscle retains measurable but markedly reduced creatine (~18% of WT); AGAT protein expression and in vitro creatine biosynthesis rates are upregulated ~3-fold and ~1.5-fold respectively in KO muscle, demonstrating compensatory induction of local creatine synthesis when SLC6A8-mediated uptake is lost. Whole-body CrT KO mice, HPLC creatine measurement, western blot (AGAT/GAMT protein), qPCR, in vitro creatine biosynthesis assay Frontiers in physiology High 25206338
2019 Macrophage Slc6a8-mediated creatine uptake reprograms macrophage polarization: creatine suppresses M(IFN-γ) (M1) effector functions by inhibiting IFN-γ-JAK-STAT1 signaling and supports M(IL-4) (M2) functions by promoting chromatin remodeling at STAT6 targets; ablation of Slc6a8 in macrophages alters these immune responses in vivo. Genetic Slc6a8 ablation in macrophages, cytokine stimulation assays, STAT1/STAT6 signaling analysis, chromatin remodeling assays, in vivo macrophage functional studies Immunity High 31399282
2021 RGX-202, a small-molecule SLC6A8 inhibitor, blocks creatine import, reduces intracellular phosphocreatine and ATP, induces tumor apoptosis, and suppresses colorectal cancer growth in xenograft, syngeneic, and PDX models; antitumor efficacy correlates with creatine kinase B expression; combination with 5-FU or the DHODH inhibitor leflunomide causes tumor regressions. In vitro creatine transport inhibition assay, xenograft/syngeneic/PDX mouse tumor models, metabolite measurement (phosphocreatine, ATP), apoptosis assays, phase 1 clinical pharmacodynamics Science advances High 34613776
2021 Leukemic cell-derived small extracellular vesicles carrying miR-19a-3p are internalized by CD8+ T cells and directly repress SLC6A8 expression, inhibiting creatine import, reducing ATP production, and impairing CD8+ T cell immune function, leading to immune escape by NPM1-mutated AML cells. sEV co-culture system, miR-19a-3p overexpression/inhibition, SLC6A8 reporter assay, creatine/ATP measurement, CD8+ T cell functional assays Journal of extracellular vesicles Medium 34807526
2020 Quantitative profiling of eight pathogenic SLC6A8 variants shows all exhibit proteostatic deficiencies (reduced expression/trafficking); two variants primarily disrupt the substrate-binding pocket (distinct from trafficking defects); structural modeling identifies mechanistic classes; 4-PBA (proteostasis regulator) enhances WT SLC6A8 activity in HEK293T cells. Transient transfection in HEK293T, creatine uptake assay, cell surface trafficking/expression quantification, structural homology modeling, temperature sensitivity assay, 4-PBA treatment, site-directed mutagenesis Biochemistry High 32207963
2023 Mass spectrometry interactome of WT SLC6A8 in HEK293T cells identified binding partners; pathogenic variants lead to enrichment of ER protein partners (retention), and two variants disrupt protein–protein interaction interfaces as revealed by in silico complex modeling; homology models of inward-facing and outward-facing conformations used to classify variant effects on the transport cycle. Co-immunoprecipitation mass spectrometry, homology modeling (inward/outward conformations), creatine uptake assay, subcellular localization (immunofluorescence), thermodynamic stability prediction Journal of molecular biology High 38070861
2021 SLC6A8 is transcriptionally upregulated by p65/NF-κB in hypoxic triple-negative breast cancer cells; SLC6A8-mediated creatine accumulation reduces mitochondrial activity and oxygen consumption, lowers ROS, and activates AKT-ERK signaling to promote survival (upregulation of Ki-67, Bcl-2; downregulation of Bax, cleaved Caspase-3). RNA-seq, siRNA knockdown, creatine uptake measurement, ROS assay, mitochondrial OCR measurement, AKT/ERK signaling western blot, xenograft mouse model Journal of experimental & clinical cancer research Medium 33990217
2007 Spatiotemporal expression of ct1 (SLC6A8 ortholog) in zebrafish embryos shows initial ubiquitous expression followed by strong expression in somites and gut, with expression in the central nervous system during segmentation but not in yolk or liver — distinct from the co-expressed creatine synthesis enzymes agat and gamt. Whole-mount in situ hybridization with histological sectioning in zebrafish embryos The International journal of developmental biology Medium 17486546

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Radiation-induced second cancers: the impact of 3D-CRT and IMRT. International journal of radiation oncology, biology, physics 957 12694826
1998 The DNA replication and damage checkpoint pathways induce transcription by inhibition of the Crt1 repressor. Cell 434 9741624
2001 X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. American journal of human genetics 303 11326334
2019 Slc6a8-Mediated Creatine Uptake and Accumulation Reprogram Macrophage Polarization via Regulating Cytokine Responses. Immunity 181 31399282
2004 High prevalence of SLC6A8 deficiency in X-linked mental retardation. American journal of human genetics 162 15154114
2019 Oncologic Outcomes Following Partial Nephrectomy and Percutaneous Ablation for cT1 Renal Masses. European urology 141 31060824
2001 Conformal radiotherapy (CRT) planning for lung cancer: analysis of intrathoracic organ motion during extreme phases of breathing. International journal of radiation oncology, biology, physics 120 11704333
2006 X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology. Human genetics 106 16738945
2011 Creatine transporter (CrT; Slc6a8) knockout mice as a model of human CrT deficiency. PloS one 95 21249153
2008 Molecular cloning and characterization of wheat calreticulin (CRT) gene involved in drought-stressed responses. Journal of experimental botany 87 18349049
2002 Cardiotrophin-1 (CT-1) can protect the adult heart from injury when added both prior to ischaemia and at reperfusion. Cardiovascular research 82 11922900
2008 AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: a review. Journal of inherited metabolic disease 78 18392746
2009 Dissociation of AGAT, GAMT and SLC6A8 in CNS: relevance to creatine deficiency syndromes. Neurobiology of disease 77 19879361
2023 Toripalimab combined with definitive chemoradiotherapy in locally advanced oesophageal squamous cell carcinoma (EC-CRT-001): a single-arm, phase 2 trial. The Lancet. Oncology 74 36990609
2019 CT-1 (Cardiotrophin-1)-Gal-3 (Galectin-3) Axis in Cardiac Fibrosis and Inflammation. Hypertension (Dallas, Tex. : 1979) 74 30612490
1999 Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes. Archives of biochemistry and biophysics 74 9882430
2008 Cloning of the cytochrome p450 reductase (crtR) gene and its involvement in the astaxanthin biosynthesis of Xanthophyllomyces dendrorhous. BMC microbiology 67 18837978
2016 OsCLT1, a CRT-like transporter 1, is required for glutathione homeostasis and arsenic tolerance in rice. The New phytologist 66 26918637
2008 CRT1, an Arabidopsis ATPase that interacts with diverse resistance proteins and modulates disease resistance to turnip crinkle virus. Cell host & microbe 66 18191794
2021 Therapeutic targeting of SLC6A8 creatine transporter suppresses colon cancer progression and modulates human creatine levels. Science advances 65 34613776
2018 Radical Versus Partial Nephrectomy for cT1 Renal Cell Carcinoma. European urology 61 30262341
2014 Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases. Molecular genetics and metabolism 55 24953403
2010 Endosome-associated CRT1 functions early in resistance gene-mediated defense signaling in Arabidopsis and tobacco. The Plant cell 53 20332379
2007 Expression and function of AGAT, GAMT and CT1 in the mammalian brain. Sub-cellular biochemistry 53 18652072
2006 Ccr4 contributes to tolerance of replication stress through control of CRT1 mRNA poly(A) tail length. Journal of cell science 53 17158920
2007 Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application. Human mutation 52 17465020
2018 Multicopy integrants of crt genes and co-expression of AMP deaminase improve lycopene production in Yarrowia lipolytica. Journal of biotechnology 51 30448359
2008 Characterization of the TaAIDFa gene encoding a CRT/DRE-binding factor responsive to drought, high-salt, and cold stress in wheat. Molecular genetics and genomics : MGG 49 18800227
2007 PIKfyve in the SGK1 mediated regulation of the creatine transporter SLC6A8. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 49 17982255
2005 Stimulation of the creatine transporter SLC6A8 by the protein kinases SGK1 and SGK3. Biochemical and biophysical research communications 46 16036218
2021 Tumour-derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8-mediated creatine import in NPM1-mutated acute myeloid leukaemia. Journal of extracellular vesicles 44 34807526
2004 Identification of new genes regulated by the Crt1 transcription factor, an effector of the DNA damage checkpoint pathway in Saccharomyces cerevisiae. The Journal of biological chemistry 44 15494396
2014 Upregulation of the creatine transporter Slc6A8 by Klotho. Kidney & blood pressure research 42 25531216
2001 CT-1 mediated cardioprotection against ischaemic re-oxygenation injury is mediated by PI3 kinase, Akt and MEK1/2 pathways. Cytokine 40 11741348
2010 The screening of SLC6A8 deficiency among Estonian families with X-linked mental retardation. Journal of inherited metabolic disease 37 24137762
2007 Severe epilepsy in X-linked creatine transporter defect (CRTR-D). Epilepsia 37 17553121
2020 Percutaneous CT- and MRI-guided Cryoablation of cT1 Renal Cell Carcinoma: Intermediate- to Long-term Outcomes in 307 Patients. Radiology 35 32633677
2008 Characterization of cyanobacterial carotenoid ketolase CrtW and hydroxylase CrtR by complementation analysis in Escherichia coli. Plant & cell physiology 35 18987067
2020 Studies on sugar transporter CRT1 reveal new characteristics that are critical for cellulase induction in Trichoderma reesei. Biotechnology for biofuels 34 32944074
2016 Soluble ST2 and Risk of Arrhythmias, Heart Failure, or Death in Patients with Mildly Symptomatic Heart Failure: Results from MADIT-CRT. Journal of cardiovascular translational research 32 27798759
2012 Contiguous deletion of SLC6A8 and BAP31 in a patient with severe dystonia and sensorineural deafness. Molecular genetics and metabolism 32 22472424
2006 Stimulation of the creatine transporter SLC6A8 by the protein kinase mTOR. Biochemical and biophysical research communications 32 16466692
2005 Molecular genetic analysis of the yeast repressor Rfx1/Crt1 reveals a novel two-step regulatory mechanism. Molecular and cellular biology 32 16107689
2022 CD47KO/CRT dual-bioengineered cell membrane-coated nanovaccine combined with anti-PD-L1 antibody for boosting tumor immunotherapy. Bioactive materials 31 36246666
2013 CDX2 regulates multiple trophoblast genes in bovine trophectoderm CT-1 cells. Molecular reproduction and development 31 23836438
2013 Loss of all three calreticulins, CRT1, CRT2 and CRT3, causes enhanced sensitivity to water stress in Arabidopsis. Plant cell reports 31 24022063
2021 SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress. Journal of experimental & clinical cancer research : CR 30 33990217
2012 Detection of variants in SLC6A8 and functional analysis of unclassified missense variants. Molecular genetics and metabolism 30 22281021
2014 Genotype-phenotype correlation of contiguous gene deletions of SLC6A8, BCAP31 and ABCD1. Clinical genetics 28 24597975
1999 Cardiotrophin-1 (CT-1): a novel hypertrophic and cardioprotective agent. International journal of experimental pathology 28 10583628
2014 Creatine transporter (SLC6A8) knockout mice display an increased capacity for in vitro creatine biosynthesis in skeletal muscle. Frontiers in physiology 27 25206338
2014 Negative regulation of the creatine transporter SLC6A8 by SPAK and OSR1. Kidney & blood pressure research 27 25531585
2007 Functional capacity and changes in the neurohormonal and cytokine status after long-term CRT in heart failure patients. International journal of cardiology 27 17582527
1996 The genomic organization of a human creatine transporter (CRTR) gene located in Xq28. Genomics 27 8661155
2021 Antimalarial drug resistance in the Central and Adamawa regions of Cameroon: Prevalence of mutations in P. falciparum crt, Pfmdr1, Pfdhfr and Pfdhps genes. PloS one 26 34411157
2018 Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene Slc6a8. Genes, brain, and behavior 25 29384270
2015 Estimated carrier frequency of creatine transporter deficiency in females in the general population using functional characterization of novel missense variants in the SLC6A8 gene. Gene 25 25861866
2017 Diagnostic value of sentinel lymph node biopsy for cT1/T2N0 tongue squamous cell carcinoma: a meta-analysis. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery 24 28900723
2015 A Nematode Calreticulin, Rs-CRT, Is a Key Effector in Reproduction and Pathogenicity of Radopholus similis. PloS one 24 26061142
2005 Carotenoid biosynthetic pathway: molecular phylogenies and evolutionary behavior of crt genes in eubacteria. Gene 24 15716108
2016 Prevalence of crt and mdr-1 mutations in Plasmodium falciparum isolates from Grande Comore island after withdrawal of chloroquine. Malaria journal 23 27527604
2018 LPA1/3 signaling mediates tumor lymphangiogenesis through promoting CRT expression in prostate cancer. Biochimica et biophysica acta. Molecular and cell biology of lipids 22 30053596
2010 Overexpression of CrtR-b2 (carotene beta hydroxylase 2) from S. lycopersicum L. differentially affects xanthophyll synthesis and accumulation in transgenic tomato plants. Transgenic research 22 20383744
2008 Modification of CEA with both CRT and TAT PTD induces potent anti-tumor immune responses in RNA-pulsed DC vaccination. Vaccine 22 18812201
2021 SLC6A8 is involved in the progression of non-small cell lung cancer through the Notch signaling pathway. Annals of translational medicine 21 33708891
2020 Classification of the Molecular Defects Associated with Pathogenic Variants of the SLC6A8 Creatine Transporter. Biochemistry 20 32207963
2020 HIF-1α regulates osteoclast activation and mediates osteogenesis during mandibular bone repair via CT-1. Oral diseases 20 33274496
2010 Language disorder with mild intellectual disability in a child affected by a novel mutation of SLC6A8 gene. Molecular genetics and metabolism 20 21144783
2008 Risk of isolated nodal failure for non-small cell lung cancer (NSCLC) treated with the elective nodal irradiation (ENI) using 3D-conformal radiotherapy (3D-CRT) techniques--a retrospective analysis. Acta oncologica (Stockholm, Sweden) 20 17851862
2005 Hard tick calreticulin (CRT) gene coding regions have only one intron with conserved positions and variable sizes. The Journal of parasitology 20 16539012
2021 Sequential chemo-hypofractionated RT versus concurrent standard CRT for locally advanced NSCLC: GRADE recommendation by the Italian Association of Radiotherapy and Clinical Oncology (AIRO). La Radiologia medica 19 33954898
2012 Downregulation of the creatine transporter SLC6A8 by JAK2. The Journal of membrane biology 19 22407360
2012 Modeling the interfacial interactions between CrtS and CrtR from Xanthophyllomyces dendrorhous , a P450 system involved in astaxanthin production. Journal of agricultural and food chemistry 19 22897793
2017 Endoplasmic reticulum stress-mediated membrane expression of CRT/ERp57 induces immunogenic apoptosis in drug-resistant endometrial cancer cells. Oncotarget 18 28938593
2016 MAZ mediates the cross-talk between CT-1 and NOTCH1 signaling during gliogenesis. Scientific reports 18 26867947
2013 Circularized RT-PCR (cRT-PCR): analysis of the 5' ends, 3' ends, and poly(A) tails of RNA. Methods in enzymology 18 24034325
2012 Mutation in the Plasmodium falciparum CRT protein determines the stereospecific activity of antimalarial cinchona alkaloids. Antimicrobial agents and chemotherapy 18 22869567
2021 Tumor-stroma ratio is a crucial histological predictor of occult cervical lymph node metastasis and survival in early-stage (cT1/2N0) oral squamous cell carcinoma. International journal of oral and maxillofacial surgery 17 34412929
2020 Predicting the risk of pT3a stage in cT1 clear cell renal cell carcinoma. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 17 33168336
2019 Biopriming of maize germination by the plant growth-promoting rhizobacterium Azospirillum lipoferum CRT1. Journal of plant physiology 17 31071544
2017 Treatment effects of Cardiotrophin-1 (CT-1) on streptozotocin-induced memory deficits in mice. Experimental gerontology 16 28285145
2012 Functional and electrophysiological characterization of four non-truncating mutations responsible for creatine transporter (SLC6A8) deficiency syndrome. Journal of inherited metabolic disease 16 22644605
1999 The dimerization/repression domain of RFX1 is related to a conserved region of its yeast homologues Crt1 and Sak1: a new function for an ancient motif. Journal of molecular biology 16 10556033
2022 Trends in Positive Surgical Margins in cT1-T2 Oral Cavity Squamous Cell Carcinoma. The Laryngoscope 15 35102568
2020 Corynebacterium glutamicum CrtR and Its Orthologs in Actinobacteria: Conserved Function and Application as Genetically Encoded Biosensor for Detection of Geranylgeranyl Pyrophosphate. International journal of molecular sciences 15 32751941
2019 Creatine transporter knockout mice (Slc6a8) show increases in serotonin-related proteins and are resilient to learned helplessness. Behavioural brain research 15 31542396
2018 Available ablation energies to treat cT1 renal cell cancer: emerging technologies. World journal of urology 15 30448873
2007 Spatiotemporal expression of the creatine metabolism related genes agat, gamt and ct1 during zebrafish embryogenesis. The International journal of developmental biology 15 17486546
2007 Molecular phylogenies and evolution of crt genes in algae. Critical reviews in biotechnology 15 17578704
2003 The cardioprotective agent urocortin induces expression of CT-1. Cardiovascular toxicology 15 14555790
2019 The mechanical effects of CRT promoting autophagy via mitochondrial calcium uniporter down-regulation and mitochondrial dynamics alteration. Journal of cellular and molecular medicine 14 30938090
2016 New orally active DNA minor groove binding small molecule CT-1 acts against breast cancer by targeting tumor DNA damage leading to p53-dependent apoptosis. Molecular carcinogenesis 14 27813185
2012 Transcriptome, proteome, and metabolome in dyssynchronous heart failure and CRT. Journal of cardiovascular translational research 14 22311562
2009 Association of molecular markers in Plasmodium falciparum crt and mdr1 with in vitro chloroquine resistance: a Philippine study. Parasitology international 14 19567229
2023 Oncological outcome of vocal cord-only radiotherapy for cT1-T2 glottic laryngeal squamous cell carcinoma. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery 12 36881167
2018 A novel SLC6A8 mutation associated with intellectual disabilities in a Chinese family exhibiting creatine transporter deficiency: case report. BMC medical genetics 12 30400883
2015 Regulation of the Na+,Cl- Coupled Creatine Transporter CreaT (SLC6A8) by the Janus Kinase JAK3. Neuro-Signals 12 26666525
2010 Applicability of the 16S-23S rDNA internal spacer for PCR detection of the phytostimulatory PGPR inoculant Azospirillum lipoferum CRT1 in field soil. Journal of applied microbiology 12 19583800
2023 Experimental and Computational Analysis of Newly Identified Pathogenic Mutations in the Creatine Transporter SLC6A8. Journal of molecular biology 11 38070861
2021 Sentinel Lymph Node Biopsy Versus Elective Node Dissection in Stage cT1-2N0 Oral Cavity Cancer. The Laryngoscope 11 34637145