title: Transport of L-glutamine, L-alanine, L-arginine and L-histidine by the neuron-specific Slc38a8 (SNAT8) in CNS.
abstract: Glutamine transporters are important for regulating levels of glutamate and GABA in the brain. To date, six members of the SLC38 family (SNATs) have been characterized and functionally subdivided them into System A (SNAT1, SNAT2 and SNAT4) and System N (SNAT3, SNAT5 and SNAT7). Here we present the first functional characterization of SLC38A8, one of the previous orphan transporters from the family, and we suggest that the encoded protein should be named SNAT8 to adhere with the SNAT nomenclature. We show that SLC38A8 has preference for transporting L-glutamine, L-alanine, L-arginine, L-histidine and L-aspartate using a Na+-dependent transport mechanism and that the functional characteristics of SNAT8 have highest similarity to the known System A transporters. We also provide a comprehensive central nervous system expression profile in mouse brain for the Slc38a8 gene and the SNAT8 protein. We show that Slc38a8 (SNAT8) is expressed in all neurons, both excitatory and inhibitory, in mouse brain using in situ hybridization and immunohistochemistry. Furthermore, proximity ligation assay shows highly similar subcellular expression of SNAT7 and SNAT8. In conclusion, the neuronal SLC38A8 has a broad amino acid transport profile and is the first identified neuronal System A transporter. This suggests a key role of SNAT8 in the glutamine/glutamate (GABA) cycle in the brain.
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Husargatan 3, SE-75124 Uppsala, Sweden. Electronic address: Maria.Hagglund@neuro.uu.se.
authors.forename: Maria G A
authors.initials: MGA
authors.lastname: Hägglund
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Husargatan 3, SE-75124 Uppsala, Sweden. Electronic address: Sofie.Hellsten@neuro.uu.se.
authors.forename: Sofie V
authors.initials: SV
authors.lastname: Hellsten
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Husargatan 3, SE-75124 Uppsala, Sweden. Electronic address: Sonchita.Bagchi@neuro.uu.se.
authors.forename: Sonchita
authors.initials: S
authors.lastname: Bagchi
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Husargatan 3, SE-75124 Uppsala, Sweden. Electronic address: Gaetan.Philippot.9847@student.uu.se.
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Philippot
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Husargatan 3, SE-75124 Uppsala, Sweden. Electronic address: Eriklofqvist@gmail.com.
authors.forename: Erik
authors.initials: E
authors.lastname: Löfqvist
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Husargatan 3, SE-75124 Uppsala, Sweden. Electronic address: Nilsson.Wictor@gmail.com.
authors.forename: Victor C O
authors.initials: VCO
authors.lastname: Nilsson
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Husargatan 3, SE-75124 Uppsala, Sweden. Electronic address: Ingal552@student.liu.se.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Almkvist
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Husargatan 3, SE-75124 Uppsala, Sweden. Electronic address: Edwinkarlsson@gmail.com.
authors.forename: Edvin
authors.initials: E
authors.lastname: Karlsson
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Husargatan 3, SE-75124 Uppsala, Sweden. Electronic address: Smitha.Sreedharan@neuro.uu.se.
authors.forename: Smitha
authors.initials: S
authors.lastname: Sreedharan
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Husargatan 3, SE-75124 Uppsala, Sweden. Electronic address: Atieh.Tafreshiha@gmail.com.
authors.forename: Atieh
authors.initials: A
authors.lastname: Tafreshiha
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Husargatan 3, SE-75124 Uppsala, Sweden. Electronic address: Robert.Fredriksson@neuro.uu.se.
authors.forename: Robert
authors.initials: R
authors.lastname: Fredriksson
mesh_terms: D000409:Alanine / Q000378:metabolism*; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D004594:Electrophysiology; D005260:Female; D005455:Fluorescent Antibody Technique; D005973:Glutamine / Q000378:metabolism*; D006639:Histidine / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D017136:Ion Transport; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010802:Phylogeny; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D012333:RNA, Messenger; D005973:Glutamine; D006639:Histidine; D001120:Arginine; D012964:Sodium; D000409:Alanine
keywords: amino acid transport; glutamine; glutamine/glutamate (GABA) cycle; neuron; transporter