Differential expression of the cationic amino acid transporter 2(B) in the adult rat brain

Braissant, Olivier; Gotoh, Tomomi; Loup, Marc; Mori, Masataka; Bachmann, C.

doi:10.1016/s0169-328x(01)00113-9

Cited by 37 publications

(19 citation statements)

References 30 publications

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“…Structures were identified according to [53-55], after staining of sections by hematoxylin (see Figure 2). In Figures 9,10 and 11 semi-quantitative levels of AGAT, GAMT and CT1 mRNA were determined based on ISH experiments, as described [56]. Levels of transcripts observed by optical microscopy are indicated by - and + signs which however do not represent a strict linear mesure of mRNA.…”

Section: Methodsmentioning

confidence: 99%

Creatine synthesis and transport during rat embryogenesis: Spatiotemporal expression of AGAT, GAMT and CT1

Braissant¹,

Henry²,

Villard³

et al. 2005

BMC Dev Biol

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110

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Background: Creatine (Cr) is synthesized by a two-step mechanism involving arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), and is taken up by cells through a specific Cr transporter, CT1. Recently, genetic defects of this pathway have been described, that lead to Cr deficiency, neurological symptoms in early infancy and severe neurodevelopmental delay. To investigate the involvement of Cr synthesis and uptake pathways during embryonic development, we determined the spatiotemporal expression of AGAT, GAMT and CT1 during the rat embryogenesis, at the mRNA and protein level.

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Section: Methodsmentioning

confidence: 99%

Creatine synthesis and transport during rat embryogenesis: Spatiotemporal expression of AGAT, GAMT and CT1

Braissant¹,

Henry²,

Villard³

et al. 2005

BMC Dev Biol

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110

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“…Attempts to treat SLC6A8-deficient patients with arginine and glycine as precursors of Cr gave some modest encouraging results in two SLC6A8-deficient patients (Chilosi et al 2008;Wilcken et al 2008), while it failed to improve the neurological status of many others (Fons et al 2008;Valayannopoulos et al 2011;van de Kamp et al 2011b). BBB and its surrounding astrocytes efficiently express cationic amino acid transporters (CATs 1 and 2B) allowing the import of arginine from periphery to the blood (Braissant et al 2001a;Braissant et al 1999). Altogether, data on the treatment of Cr-deficient patients indicate that Cr is taken up in limited amounts by CNS from periphery, and that this modest transport of Cr through BBB most probably exclusively occurs through SLC6A8 Braissant and Henry 2008) (Fig.…”

Section: Cr and Gaa Through Bbb And Bcsfb And Within Cnsmentioning

confidence: 99%

Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers

Braissant

2012

J of Inher Metab Disea

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While it was thought that most of cerebral creatine is of peripheral origin, AGAT and GAMT are well expressed in CNS where brain cells synthesize creatine. While the creatine transporter SLC6A8 is expressed by microcapillary endothelial cells (MCEC) at blood-brain barrier (BBB), it is absent from their surrounding astrocytes. This raised the concept that BBB has a limited permeability for peripheral creatine, and that the brain supplies a part of its creatine by endogenous synthesis. This review brings together the latest data on creatine and guanidinoacetate transport through BBB and blood-CSF barrier (BCSFB) with the clinical evidence of AGAT-, GAMT- and SLC6A8-deficient patients, in order to delineate a clearer view on the roles of BBB and BCSFB in the transport of creatine and guanidinoacetate between periphery and CNS, and on brain synthesis and transport of creatine. It shows that in physiological conditions, creatine is taken up by CNS from periphery through SLC6A8 at BBB, but in limited amounts, and that CNS also needs its own creatine synthesis. No uptake of guanidinoacetate from periphery occurs at BBB except under GAMT deficiency, but a net exit of guanidinoacetate seems to occur from CSF to blood at BCSFB, predominantly through the taurine transporter TauT.

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“…The brain capacity for Cr synthesis would thus depend on the efficient supply of arginine, the limiting substrate for Cr synthesis, from blood to CNS, and then also on local trafficking of arginine between brain cells. We and others have shown that cationic amino acid transporters (CATs) might fulfill these roles in the brain, as CAT1 is expressed in MCEC as well as ubiquitously in neuronal and glial cells, as CAT2(B) is present in neurons and oligodendrocytes, and as CAT3 is restricted to neurons (Braissant et al 1999;Hosokawa et al 1999;Braissant et al 2001a).…”

Section: Creatine In Cns: Endogenous Synthesis Versus Uptake From Permentioning

confidence: 99%

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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Differential expression of the cationic amino acid transporter 2(B) in the adult rat brain

Cited by 37 publications

References 30 publications

Creatine synthesis and transport during rat embryogenesis: Spatiotemporal expression of AGAT, GAMT and CT1

Creatine synthesis and transport during rat embryogenesis: Spatiotemporal expression of AGAT, GAMT and CT1

Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers

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

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