Slc6a1

Summary

Gene Symbol: Slc6a1
Description: solute carrier family 6 (neurotransmitter transporter, GABA), member 1
Alias: A730043E01, GABATHG, GABATR, GAT-1, Gabt, Gabt1, Gat1, XT-1, Xtrp1, sodium- and chloride-dependent GABA transporter 1, gamma-aminobutyric acid (GABA-A) transporter 1, solute carrier family 6 member 1
Species: mouse
Products:     Slc6a1

Top Publications

  1. Liu Q, Lopez Corcuera B, Mandiyan S, Nelson H, Nelson N. Molecular characterization of four pharmacologically distinct gamma-aminobutyric acid transporters in mouse brain [corrected]. J Biol Chem. 1993;268:2106-12 pubmed
    ..4 mM. The newly cloned GABA transporters were compared with two previously cloned GABA transporters, GAT1 and GAT2, in terms of molecular and pharmacological properties...
  2. Liu G, Cai G, Cai Y, Sheng Z, Jiang J, Mei Z, et al. Reduced anxiety and depression-like behaviors in mice lacking GABA transporter subtype 1. Neuropsychopharmacology. 2007;32:1531-9 pubmed
    Gamma-aminobutyric acid (GABA) transporter subtype 1 (GAT1), which transports extracellular GABA into presynaptic neurons, plays an important regulatory role in the function of GABAergic systems...
  3. Imoukhuede P, Moss F, Michael D, Chow R, Lester H. Ezrin mediates tethering of the gamma-aminobutyric acid transporter GAT1 to actin filaments via a C-terminal PDZ-interacting domain. Biophys J. 2009;96:2949-60 pubmed publisher
    ..We determined the interactions that confine GAT1 at the membrane by investigating the lateral mobility of GAT1-yellow fluorescent protein-8 (YFP8) expressed in ..
  4. Jensen K, Chiu C, Sokolova I, Lester H, Mody I. GABA transporter-1 (GAT1)-deficient mice: differential tonic activation of GABAA versus GABAB receptors in the hippocampus. J Neurophysiol. 2003;90:2690-701 pubmed
    ..The predominant neuronal GABA transporter GAT1 is localized in GABAergic axons and nerve terminals, where it is thought to influence GABAergic synaptic ..
  5. Chiu C, Jensen K, Sokolova I, Wang D, Li M, Deshpande P, et al. 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. 2002;22:10251-66 pubmed
    GABA transporter subtype 1 (GAT1) molecules were counted near GABAergic synapses, to a resolution of approximately 0.5 microm...
  6. Chiu C, Brickley S, Jensen K, Southwell A, McKinney S, Cull Candy S, et al. GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. J Neurosci. 2005;25:3234-45 pubmed
    GABA transporter subtype 1 (GAT1) knock-out (KO) mice display normal reproduction and life span but have reduced body weight (female, -10%; male, -20%) and higher body temperature fluctuations in the 0.2-1.5/h frequency range...
  7. Cai Y, Cai G, Liu G, Cai Q, Shi J, Shi J, et al. Mice with genetically altered GABA transporter subtype I (GAT1) expression show altered behavioral responses to ethanol. J Neurosci Res. 2006;84:255-67 pubmed
    ..GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites in the CNS and regulates GABAergic transmissions...
  8. McHugh E, Zhu W, Milgram S, Mager S. The GABA transporter GAT1 and the MAGUK protein Pals1: interaction, uptake modulation, and coexpression in the brain. Mol Cell Neurosci. 2004;26:406-17 pubmed
    ..two-hybrid system to identify proteins that associate with the carboxy-terminus of the neuronal GABA transporter GAT1. We found an interaction between GAT1 and the MAGUK protein Pals1...
  9. Liu G, Liu S, Cai G, Sheng Z, Cai Y, Jiang J, et al. Reduced aggression in mice lacking GABA transporter subtype 1. J Neurosci Res. 2007;85:649-55 pubmed
    ..As a key regulator of central GABAergic activity, dysfunction of the GABA transporter subtype 1 (GAT1) represents a potential mechanism mediating pathologic aggression...

More Information

Publications60

  1. Bragina L, Marchionni I, Omrani A, Cozzi A, Pellegrini Giampietro D, Cherubini E, et al. GAT-1 regulates both tonic and phasic GABA(A) receptor-mediated inhibition in the cerebral cortex. J Neurochem. 2008;105:1781-93 pubmed publisher
  2. Gong N, Li Y, Cai G, Niu R, Fang Q, Wu K, et al. GABA transporter-1 activity modulates hippocampal theta oscillation and theta burst stimulation-induced long-term potentiation. J Neurosci. 2009;29:15836-45 pubmed publisher
    ..that in the CA1 region of mouse hippocampus, pharmacological blockade or genetic deletion of GABA transporter-1 (GAT1) specifically impaired long-term potentiation (LTP) induced by theta burst stimulation, but had no effect on LTP ..
  3. Liu Q, Mandiyan S, Nelson H, Nelson N. A family of genes encoding neurotransmitter transporters. Proc Natl Acad Sci U S A. 1992;89:6639-43 pubmed
    ..The Drosophila gene contains an intron that starts at a position identical to the corresponding positions of all the mammalian genes of the family. ..
  4. Cope D, Di Giovanni G, Fyson S, Orbán G, Errington A, Lorincz M, et al. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med. 2009;15:1392-8 pubmed publisher
    ..These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic importance and highlight potential therapeutic targets for the treatment of absence epilepsy. ..
  5. Höglund P, Adzic D, Scicluna S, Lindblom J, Fredriksson R. The repertoire of solute carriers of family 6: identification of new human and rodent genes. Biochem Biophys Res Commun. 2005;336:175-89 pubmed
    ..This paper presents an overall overview of the gene repertoire of the SLC6 gene family and its expression profile in rats. ..
  6. Avila M, Real M, Guirado S. Patterns of GABA and GABA Transporter-1 immunoreactivities in the developing and adult mouse brain amygdala. Brain Res. 2011;1388:1-11 pubmed publisher
    We used immunohistochemistry to analyze the spatiotemporal patterns of GABA and GABA Transporter-1 (GAT1) immunoreactivities in the developing and adult mouse amygdala...
  7. Qiu F, Jiang H, Xiang M. A comprehensive negative regulatory program controlled by Brn3b to ensure ganglion cell specification from multipotential retinal precursors. J Neurosci. 2008;28:3392-403 pubmed publisher
    ..Our data suggest that Brn3b specifies the RGC fate from multipotential precursors not only by promoting RGC differentiation but also by suppressing non-RGC differentiation programs as a safeguard mechanism. ..
  8. Xu Y, Cai Y, Gong N, Chen C, Wu Y, Zhang Nunes S, et al. Homeostatic plasticity of GABAergic synaptic transmission in mice lacking GAT1. Biochem Biophys Res Commun. 2007;361:499-504 pubmed
    GABA transporter-1 (GAT1) plays a key role in GABA reuptake, and deletion of GAT1 leads to a largely increased GABA-induced tonic conductance in the GAT1(-/-) mice...
  9. Perona M, Waters S, Hall F, Sora I, Lesch K, Murphy D, et al. Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions. Behav Pharmacol. 2008;19:566-74 pubmed publisher
    ..side effects via blockade of the plasma membrane transporters for serotonin (SERT/SLC6A2), norepinephrine (NET/SLC6A1), and dopamine (DAT/SLC6A3). Many antidepressants block several of these transporters; some are more selective...
  10. Hu J, Fei J, Reutter W, Fan H. Involvement of sialic acid in the regulation of ?--aminobutyric acid uptake activity of ?-aminobutyric acid transporter 1. Glycobiology. 2011;21:329-39 pubmed publisher
    ..The GAT1 belongs to the family of Na(+)- and Cl(-)-coupled transport proteins, which possess 12 putative transmembrane (TM) ..
  11. Byun K, Kim J, Cho S, Hutchinson B, Yang S, Kang K, et al. Alteration of the glutamate and GABA transporters in the hippocampus of the Niemann-Pick disease, type C mouse using proteomic analysis. Proteomics. 2006;6:1230-6 pubmed
    ..In conclusion, our data may provide insight into the understanding of the basic mechanism through perturbation of protein networks and neurotransporter systems in a single gene knockout model of NPC disease. ..
  12. Hu J, Ma Y, Yang N, Mei Z, Zhang M, Fei J, et al. Up-regulation of gamma-aminobutyric acid transporter I mediates ethanol sensitivity in mice. Neuroscience. 2004;123:807-12 pubmed
    ..pre-injected with a competitive or a noncompetitive antagonist of gamma-aminobutyric acid transporter subtype 1 (GAT1) showed high sensitivity to the sedative/hypnotic effects of ethanol...
  13. Kim J, Kosaka Y, Shimizu Okabe C, Niizaki A, Takayama C. Characteristic development of the GABA-removal system in the mouse spinal cord. Neuroscience. 2014;262:129-42 pubmed publisher
    ..4) After synapse formation, GAT-3 may continue to remove GABA from immature and mature synaptic clefts into the processes of astrocytes. (5) Development of the GABA-removal system may be completed by P21. ..
  14. Stephan J, Friauf E. Functional analysis of the inhibitory neurotransmitter transporters GlyT1, GAT-1, and GAT-3 in astrocytes of the lateral superior olive. Glia. 2014;62:1992-2003 pubmed publisher
    ..Thus, neuronal signaling in the LSO appears to be more versatile than previously thought. GLIA 2014;62:1992-2003. ..
  15. Masocha W. Comprehensive analysis of the GABAergic system gene expression profile in the anterior cingulate cortex of mice with Paclitaxel-induced neuropathic pain. Gene Expr. 2015;16:145-53 pubmed publisher
    ..GAT-1 is a potential therapeutic target for managing paclitaxel-induced neuropathic pain. ..
  16. Evans J, Frostholm A, Rotter A. Embryonic and postnatal expression of four gamma-aminobutyric acid transporter mRNAs in the mouse brain and leptomeninges. J Comp Neurol. 1996;376:431-46 pubmed
  17. Shi J, Cai Y, Liu G, Gong N, Liu Z, Xu T, et al. Enhanced learning and memory in GAT1 heterozygous mice. Acta Biochim Biophys Sin (Shanghai). 2012;44:359-66 pubmed publisher
    ..termination of GABA transmission is through the action of a family of membrane proteins, called GABA transporters (GAT1-4). It is well established that GABA system is involved in the modulation of memory...
  18. Milanese M, Bonifacino T, Fedele E, Rebosio C, Cattaneo L, Benfenati F, et al. Exocytosis regulates trafficking of GABA and glycine heterotransporters in spinal cord glutamatergic synapses: a mechanism for the excessive heterotransporter-induced release of glutamate in experimental amyotrophic lateral sclerosis. Neurobiol Dis. 2015;74:314-24 pubmed publisher
  19. Bassett E, Pontoriero G, Feng W, Marquardt T, Fini M, Williams T, et al. Conditional deletion of activating protein 2alpha (AP-2alpha) in the developing retina demonstrates non-cell-autonomous roles for AP-2alpha in optic cup development. Mol Cell Biol. 2007;27:7497-510 pubmed
    ..Additional expression analyses showed that multiple AP-2 proteins are present in the developing retina, which will be important to future studies. ..
  20. Ma Y, Hu J, Zhou X, Zeng R, Mei Z, Fei J, et al. Transgenic mice overexpressing gamma-aminobutyric acid transporter subtype I develop obesity. Cell Res. 2000;10:303-10 pubmed
    ..This preliminary finding indicates that the inappropriate level of gamma-aminobutyric acid transporters may be directly or indirectly involved in the pathogenic mechanism underlying certain types of obesity. ..
  21. Jursky F, Nelson N. Developmental expression of the neurotransmitter transporter GAT3. J Neurosci Res. 1999;55:394-9 pubmed
    ..GAT3 was localized to the meninges in developmental stages where two other GABA transporters, GAT1 and GAT4, were adjacently expressed. In later developmental stages, only GAT3 remained in this area...
  22. Guimera J, Weisenhorn D, Wurst W. Megane/Heslike is required for normal GABAergic differentiation in the mouse superior colliculus. Development. 2006;133:3847-57 pubmed
    ..Vertebrate h/E(spl)-related genes can no longer be regarded solely as a factors that confer generic neurogenic properties, but as key components for the subtype-neuronal identity in the mammalian CNS. ..
  23. Jin X, Huang F, Yang N, Lu B, Fei J, Guo L. GABA transporter 1 transcriptional starting site exhibiting tissue specific difference. Cell Res. 2001;11:161-3 pubmed
    GABA transporter 1(GAT1) takes important roles in multiple physiological processes through the uptake and release of GABA, but the regulation of GAT1 gene expression in different tissues is rarely known...
  24. Wang Y, Luo Q, Xu Y, Feng D, Fei J, Cheng Q, et al. Gamma-aminobutyric acid transporter 1 negatively regulates T cell activation and survival through protein kinase C-dependent signaling pathways. J Immunol. 2009;183:3488-95 pubmed publisher
    ..In addition, our data reveal that GAT-1 expression on T cells is modulated by PKC activation. Taken together, the data show that GAT-1 negatively regulates T cell activation and survival through PKC-dependent signaling pathways. ..
  25. Wang Y, Feng D, Liu G, Luo Q, Xu Y, Lin S, et al. Gamma-aminobutyric acid transporter 1 negatively regulates T cell-mediated immune responses and ameliorates autoimmune inflammation in the CNS. J Immunol. 2008;181:8226-36 pubmed
    ..These findings indicate that GAT-1 is a critical modulator in T cell-mediated immune responses and in EAE pathogenesis. ..
  26. Kwakowsky A, Schwirtlich M, Kooy F, Abrahám I, Mate Z, Katarova Z, et al. GABA neurotransmitter signaling in the developing mouse lens: dynamic regulation of components and functionality. Dev Dyn. 2008;237:3830-41 pubmed publisher
    ..The functionality of GABAR was verified by calcium imaging in whole lenses. Our data suggest that GABA synthesized locally by GAD, acts through GABA receptors by modulating the intracellular calcium levels. ..
  27. Guo C, Stella S, Hirano A, Brecha N. Plasmalemmal and vesicular gamma-aminobutyric acid transporter expression in the developing mouse retina. J Comp Neurol. 2009;512:6-26 pubmed publisher
    ..These findings demonstrate that GABA uptake and release are initially established in the inner retina during the first postnatal week and that these systems subsequently mature in the outer retina during the second postnatal week. ..
  28. Kirmse K, Dvorzhak A, Kirischuk S, Grantyn R. GABA transporter 1 tunes GABAergic synaptic transmission at output neurons of the mouse neostriatum. J Physiol. 2008;586:5665-78 pubmed publisher
    ..We conclude that in the murine neostriatum GAT-1 operates in a net uptake mode. It prevents the persistent activation of presynaptic GABA(B)Rs (P12-34) and prevents (P7-14) or reduces (P19-34) tonic postsynaptic GABA(A)R activity. ..
  29. Hu J, Zhang J, Ma Y, Jiang J, Yang N, Li X, et al. Impaired reproduction in transgenic mice overexpressing Gamma-aminobutyric acid transporter I (GAT1). Cell Res. 2004;14:54-9 pubmed
    ..GABA transporter I (GAT1) also existed in testis and sperm, but its physiological function was unknown...
  30. Li S, Mo Z, Yang X, Price S, Shen M, Xiang M. Foxn4 controls the genesis of amacrine and horizontal cells by retinal progenitors. Neuron. 2004;43:795-807 pubmed
    ..Our data suggest a model in which Foxn4 cooperates with other key retinogenic factors to mediate the multipotent differentiation of retinal progenitors. ..
  31. Bagley E, Hacker J, Chefer V, Mallet C, McNally G, Chieng B, et al. Drug-induced GABA transporter currents enhance GABA release to induce opioid withdrawal behaviors. Nat Neurosci. 2011;14:1548-54 pubmed publisher
    ..These data provide, to the best of our knowledge, the first evidence that dysregulation of a neurotransmitter transporter current is important for the maladaptive plasticity that underlies opiate withdrawal. ..
  32. Moss F, Imoukhuede P, Scott K, Hu J, Jankowsky J, Quick M, et al. GABA transporter function, oligomerization state, and anchoring: correlates with subcellularly resolved FRET. J Gen Physiol. 2009;134:489-521 pubmed publisher
    ..Thus, pixel-by-pixel NFRET analysis resolved three distinct forms of GAT1: dimers, high-order oligomers, and transporters associated via PDZ-mediated interactions with the actin ..
  33. Xu X, Qu W, Bian M, Huang F, Fei J, Urade Y, et al. Essential roles of GABA transporter-1 in controlling rapid eye movement sleep and in increased slow wave activity after sleep deprivation. PLoS ONE. 2013;8:e75823 pubmed publisher
    ..GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites for GABA and regulates GABAergic transmission in the brain...
  34. Anderson C, Kidd P, Eskandari S. GATMD: γ-aminobutyric acid transporter mutagenesis database. Database (Oxford). 2010;2010:baq028 pubmed publisher
    Since the cloning of the first γ-aminobutyric acid (GABA) transporter (GAT1; SLC6A1) from rat brain in 1990, more than 50 published studies have provided structure-function information on investigator-designed rat and mouse GAT1 ..
  35. Yang P, Cai G, Cai Y, Fei J, Liu G. Gamma aminobutyric acid transporter subtype 1 gene knockout mice: a new model for attention deficit/hyperactivity disorder. Acta Biochim Biophys Sin (Shanghai). 2013;45:578-85 pubmed publisher
    ..Our previous studies have demonstrated that the gamma aminobutyric acid transporter subtype 1 (GAT1) gene knockout (ko) mouse (gat1-/-) is hyperactive and exhibited impaired memory performance in the Morris water ..
  36. Chen L, Yang X, Zhou X, Wang C, Gong X, Chen B, et al. Hyperactivity and impaired attention in Gamma aminobutyric acid transporter subtype 1 gene knockout mice. Acta Neuropsychiatr. 2015;27:368-74 pubmed publisher
    ..So, the study of the GAT-1-/- mice may provide new insights into the mechanisms and the discovery of novel therapeutics for the treatment of ADHD. ..
  37. Xu B, Hsu P, Stark K, Karayiorgou M, Gogos J. Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion. Cell. 2013;152:262-75 pubmed publisher
    ..Reduction of miR-185 also has milder age- and region-specific effects on the expression of some Golgi-related genes. Our findings illuminate the contribution of microRNAs in psychiatric disorders and cognitive dysfunction. ..
  38. Yu Z, Fang Q, Xiao X, Wang Y, Cai Y, Cao H, et al. GABA transporter-1 deficiency confers schizophrenia-like behavioral phenotypes. PLoS ONE. 2013;8:e69883 pubmed publisher
    ..In this study, we took advantage of GABA transporter 1 (GAT1) knockout (KO) mouse, a unique animal model with elevated ambient GABA, to study the schizophrenia-related ..
  39. Krause S, Schwarz W. Identification and selective inhibition of the channel mode of the neuronal GABA transporter 1. Mol Pharmacol. 2005;68:1728-35 pubmed
    The function of GAT1, the transporter for the inhibitory neurotransmitter GABA, is characterized by expression in Xenopus laevis oocytes and measurements of GABA-induced uptake of [3H]GABA, 22Na+, and 36Cl-, and GABA-evoked currents under ..
  40. Ma Y, Zhou X, Duan S, Hu J, Lu B, Yu Y, et al. Overexpression of gamma-aminobutyric acid transporter subtype I leads to cognitive deterioration in transgenic mice. Acta Pharmacol Sin. 2001;22:340-8 pubmed
    To explore the physiological role of gamma-aminobutyric acid transporter subtype I (GAT1) in cognition. Transgenic mice were produced by pronuclei microinjection method...
  41. Curley A, Eggan S, Lazarus M, Huang Z, Volk D, Lewis D. Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: implications for schizophrenia. Neurobiol Dis. 2013;50:179-86 pubmed publisher
    ..is responsible for most cortical GABA synthesis, are accompanied by lower levels of GABA membrane transporter 1 (GAT1) mRNA...
  42. Raiteri L, Stigliani S, Patti L, Usai C, Bucci G, Diaspro A, et al. Activation of gamma-aminobutyric acid GAT-1 transporters on glutamatergic terminals of mouse spinal cord mediates glutamate release through anion channels and by transporter reversal. J Neurosci Res. 2005;80:424-33 pubmed
    ..Activation of these GABA transporters elicits release of glutamate partially by reversal of glutamate transporters present on glutamatergic terminals and largely through anion channels. ..
  43. Ango F, Di Cristo G, Higashiyama H, Bennett V, Wu P, Huang Z. Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at purkinje axon initial segment. Cell. 2004;119:257-72 pubmed
    ..Disruption of NF186-ankyrinG interactions at AIS reduced pinceau synapse formation. These results implicate ankyrin-based localization of L1CAMs in subcellular organization of GABAergic synapses. ..
  44. Hu J, Yang N, Ma Y, Zhou X, Zhang X, Jiang J, et al. Decrease of morphine-induced reward effects and withdrawal symptoms in mice overexpressing gamma-aminobutyric acid transporter I. J Neurosci Res. 2003;74:614-21 pubmed
    ..c.) injection. We generated GABA transporter I (GAT1)-overexpressing mice to investigate whether the GABAergic system and GABA transporter are involved in morphine-..
  45. Zhang J, Gui Y, Yuan T, Bian C, Guo L. Expression of GAT1 in male reproductive system and its effects on reproduction in mice. Syst Biol Reprod Med. 2009;55:175-80 pubmed publisher
    The present study was carried out to identify GABA (gamma-aminobutyric acid) transport protein I (GAT1) in male reproductive organs and to study the effect of GAT1 overexpression on the male reproductive system in GAT1 transgenic mice (TG)..
  46. Nagatomo K, Ueda Y, Doi T, Takaki M, Tsuru N. Functional role of GABA transporters for kindling development in GLAST KO mice. Neurosci Res. 2007;57:319-21 pubmed
  47. Dávila J, Real M, Olmos L, Legaz I, Medina L, Guirado S. Embryonic and postnatal development of GABA, calbindin, calretinin, and parvalbumin in the mouse claustral complex. J Comp Neurol. 2005;481:42-57 pubmed
  48. El Mestikawy S, Giros B, Pohl M, Hamon M, Kingsmore S, Seldin M, et al. Characterization of an atypical member of the Na+/Cl(-)-dependent transporter family: chromosomal localization and distribution in GABAergic and glutamatergic neurons in the rat brain. J Neurochem. 1994;62:445-55 pubmed
    ..The gene encoding for XT1 is localized to the mouse chromosome 3 in the vicinity of the locus for the mouse neurological disorder spastic (spa). ..
  49. Romei C, Sabolla C, Raiteri L. High-affinity GABA uptake by neuronal GAT1 transporters provokes release of [(3)H]GABA by homoexchange and through GAT1-independent Ca(2+)-mediated mechanisms. Neuropharmacology. 2015;88:164-70 pubmed publisher
    ..Influx of GABA through GAT1 transporters stimulated efflux of [(3)H]GABA in a concentration-dependent manner (EC50 ∼ 3 μM)...
  50. Ma Y, Hu J, Zhou X, Mei Z, Fei J, Guo L. Gamma-aminobutyric acid transporter (GAT1) overexpression in mouse affects the testicular morphology. Cell Res. 2000;10:59-69 pubmed
    ..Reduced number of spermatids was also found in some seminiferous tubules. Our results clearly demonstrate the presence of GAT1 in mouse testis and imply that GAT1 is possibly involved in testicular function.
  51. Ruiz M, Egal H, Sarthy V, Qian X, Sarkar H. Cloning, expression, and localization of a mouse retinal gamma-aminobutyric acid transporter. Invest Ophthalmol Vis Sci. 1994;35:4039-48 pubmed
    ..The mouse retinal GAT-1 cDNA encodes a Na(+)-dependent, high-affinity GABA transporter that is mainly expressed in a subset of mouse retinal inter neurons. ..