Expression and possible role of creatine transporter in the brain and at the blood‐cerebrospinal fluid barrier as a transporting protein of guanidinoacetate, an endogenous convulsant

• Published in: Journal of neurochemistry 2008-11, Vol.107 (3), p.768-778
• Main Authors: Tachikawa, Masanori, Fujinawa, Jun, Takahashi, Masato, Kasai, Yasuyuki, Fukaya, Masahiro, Sakai, Kazuhisa, Yamazaki, Maya, Tomi, Masatoshi, Watanabe, Masahiko, Sakimura, Kenji, Terasaki, Tetsuya, Hosoya, Ken‐ichi
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Biological and medical sciences; Biological Transport; Blood-Brain Barrier - metabolism; blood‐cerebrospinal fluid barrier; Brain - metabolism; Cell Line; Cellular biology; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges; Cerebrospinal Fluid - chemistry; Cerebrospinal Fluid - metabolism; choroid plexus; Choroid Plexus - metabolism; Convulsants - metabolism; convulsion; Convulsions & seizures; creatine transporter; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Epithelial Cells - metabolism; Epithelial Cells - ultrastructure; expression; Fundamental and applied biological sciences. Psychology; Glycine - analogs & derivatives; Glycine - metabolism; guanidinoacetate; Humans; Immunoblotting; Immunohistochemistry; In Situ Hybridization; Male; Medical sciences; Membrane Transport Proteins - metabolism; Mice; Microvilli - metabolism; Neurology; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Vertebrates: nervous system and sense organs; Xenopus laevis
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05652.x

Little is known about the cerebral distribution and clearance of guanidinoacetate (GAA), the accumulation of which induces convulsions. The purpose of the present study was to identify creatine transporter (CRT)‐mediated GAA transport and to clarify its cerebral expression and role in GAA efflux transport at the blood‐cerebrospinal fluid barrier (BCSFB). CRT mediated GAA transport with a Km value of 269 μM/412 μM which was approximately 10‐fold greater than that of CRT for creatine. There was wide and distinct cerebral expression of CRT and localization of CRT on the brush‐border membrane of choroid plexus epithelial cells. The in vivo elimination clearance of GAA from the CSF was 13‐fold greater than that of d‐mannitol reflecting bulk flow of the CSF. This process was partially inhibited by creatine. The characteristics of GAA uptake by isolated choroid plexus and an immortalized rat choroid plexus epithelial cell line (TR‐CSFB cells) used as an in vitro model of BCSFB are partially consistent with those of CRT. These results suggest that CRT plays a role in the cerebral distribution of GAA and GAA uptake by the choroid plexus. However, in the presence of endogenous creatine in the CSF, CRT may make only a limited contribution to the GAA efflux transport at the BCSFB.