Immunohistochemical localisation of the creatine transporter in the rat brain

Mak, C.F.W.; Waldvogel, Henry J.; Dodd, Joanna R.; Gilbert, Raymond; Lowe, Matthew; Birch, Nigel P.; Faull, Richard L.M.; Christie, David L.

doi:10.1016/j.neuroscience.2009.06.065

Cited by 58 publications

(81 citation statements)

References 36 publications

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“…In vivo, mouse and rat CNS can take up Cr from the blood against its concentration gradient (Ohtsuki et al 2002;Perasso et al 2003). SLC6A8 is expressed throughout the main regions of adult mammalian brain (Schloss et al 1994;Happe and Murrin 1995;Braissant et al 2001b;Tachikawa et al 2008;Mak et al 2009). In the first detailed analyses of Cr transporter expression in CNS, it was demonstrated that SLC6A8 is found in neurons and oligodendrocytes but, in contrast to AGAT and GAMT, cannot be detected in astrocytes ( Fig.…”

Section: Agat Gamt and Slc6a8 In Cnsmentioning

confidence: 99%

“…In the first detailed analyses of Cr transporter expression in CNS, it was demonstrated that SLC6A8 is found in neurons and oligodendrocytes but, in contrast to AGAT and GAMT, cannot be detected in astrocytes ( Fig. 1; Braissant et al 2001b), except for very rare ones in cerebellum (Mak et al 2009). This holds true also for the retina, where SLC6A8 is expressed in retinal neurons, but not in astrocytes (Nakashima et al 2004;Acosta et al 2005).…”

Section: Agat Gamt and Slc6a8 In Cnsmentioning

confidence: 99%

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Creatine deficiency syndromes and the importance of creatine synthesis in the brain

et al. 2011

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Creatine deficiency syndromes, due to deficiencies in AGAT, GAMT (creatine synthesis pathway) or SLC6A8 (creatine transporter), lead to complete absence or very strong decrease of creatine in CNS as measured by magnetic resonance spectroscopy. Brain is the main organ affected in creatine-deficient patients, who show severe neurodevelopmental delay and present neurological symptoms in early infancy. AGAT-and GAMT-deficient patients can be treated by oral creatine supplementation which improves their neurological status, while this treatment is inefficient on SLC6A8-deficient patients. While it has long been thought that most, if not all, of brain creatine was of peripheral origin, the past years have brought evidence that creatine can cross blood-brain barrier, however, only with poor efficiency, and that CNS must ensure parts of its creatine needs by its own endogenous synthesis. Moreover, we showed very recently that in many brain structures, including cortex and basal ganglia, AGAT and GAMT, while found in every brain cell types, are not coexpressed but are rather expressed in a dissociated way. This suggests that to allow creatine synthesis in these structures, guanidinoacetate must be transported from AGAT-to GAMT-expressing cells, most probably through SLC6A8. This new understanding of creatine metabolism and transport in CNS will not only allow a better comprehension of brain consequences of creatine deficiency syndromes, but will also contribute to better decipher creatine roles in CNS, not only in energy as ATP regeneration and buffering, but also in its recently suggested functions as neurotransmitter or osmolyte.

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Section: Agat Gamt and Slc6a8 In Cnsmentioning

confidence: 99%

Section: Agat Gamt and Slc6a8 In Cnsmentioning

confidence: 99%

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

et al. 2011

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“…The carrier is expressed in diverse tissues including brain, retina, skeletal muscle, heart, and several epithelia [6,7,8,9]. Loss of function mutations of SLC6A8 result in mental retardation with seizures [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27].…”

Section: Introductionmentioning

confidence: 99%

Regulation of the Na<sup>+</sup>,Cl<sup>-</sup> Coupled Creatine Transporter CreaT (SLC6A8) by the Janus Kinase JAK3

2015

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Background: The creatine transporter CreaT (SLC6A8), a Na⁺,Cl^- coupled transporter is expressed in diverse tissues including the brain. Genetic defects of SLC6A8 result in mental retardation with seizures. The present study explored the regulation of CreaT by Janus kinase JAK3, which is expressed in a variety of tissues including the brain and participates in the regulation of cell survival and differentiation of neuronal precursor cells. Methods: CreaT was expressed in Xenopus laevis oocytes with or without wild-type JAK3, constitutively active ^A568VJAK3 and inactive ^K851AJAK3. Creatine transport in those oocytes was quantified utilizing dual electrode voltage clamp. Results: Electrogenic creatine transport was observed in CreaT expressing oocytes but not in water-injected oocytes. In CreaT expressing oocytes co-expression of JAK3 or ^A568VJAK3, but not co-expression of ^K851AJAK3 was followed by a significant decrease of creatine induced current. According to kinetic analysis JAK3 significantly decreased the maximal creatine transport rate. In CreaT and JAK3 expressing oocytes the creatine induced current was significantly increased by JAK3 inhibitor WHI-P154 (22 µM). Conclusion: JAK3 is a powerful negative regulator of the creatine transporter CreaT.

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“…Carriers expressed in both, brain and kidney include the widely expressed creatine transporter CreaT (Slc6A8) [25,26,27,28], a member of the Na + ,Cl - coupled transporter superfamily for neurotransmitters (e.g. dopamine, GABA, serotonin and norepinephrine), amino acids (e.g.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of the Creatine Transporter Slc6A8 by Klotho

Almilaji

Sopjani

Elvira

et al. 2014

Kidney Blood Press Res

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Background/Aims: The transmembrane Klotho protein contributes to inhibition of 1,25(OH)₂D₃ formation. The extracellular domain of Klotho protein could function as an enzyme with e.g. β-glucuronidase activity, be cleaved off and be released into blood and cerebrospinal fluid. Klotho regulates several cellular transporters. Klotho protein deficiency accelerates the appearance of age related disorders including neurodegeneration and muscle wasting and eventually leads to premature death. The main site of Klotho protein expression is the kidney. Klotho protein is also appreciably expressed in other tissues including chorioid plexus. The present study explored the effect of Klotho protein on the creatine transporter CreaT (Slc6A8), which participates in the maintenance of neuronal function and survival. Methods: To this end cRNA encoding Slc6A8 was injected into Xenopus oocytes with and without additional injection of cRNA encoding Klotho protein. Creatine transporter CreaT (Slc6A8) activity was estimated from creatine induced current determined by two-electrode voltage-clamp. Results: Coexpression of Klotho protein significantly increased creatine-induced current in Slc6A8 expressing Xenopus oocytes. Coexpression of Klotho protein delayed the decline of creatine induced current following inhibition of carrier insertion into the cell membrane by brefeldin A (5 µM). The increase of creatine induced current by coexpression of Klotho protein in Slc6A8 expressing Xenopus oocytes was reversed by β-glucuronidase inhibitor (DSAL). Similarly, treatment of Slc6A8 expressing Xenopus oocytes with recombinant human alpha Klotho protein significantly increased creatine induced current. Conclusion: Klotho protein up-regulates the activity of creatine transporter CreaT (Slc6A8) by stabilizing the carrier protein in the cell membrane, an effect requiring β-glucuronidase activity of Klotho protein.

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Immunohistochemical localisation of the creatine transporter in the rat brain

Cited by 58 publications

References 36 publications

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

Regulation of the Na<sup>+</sup>,Cl<sup>-</sup> Coupled Creatine Transporter CreaT (SLC6A8) by the Janus Kinase JAK3

Upregulation of the Creatine Transporter Slc6A8 by Klotho

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