title: System A transporter SAT2 mediates replenishment of dendritic glutamate pools controlling retrograde signaling by glutamate.
abstract: Glutamate mediates several modes of neurotransmission in the central nervous system including recently discovered retrograde signaling from neuronal dendrites. We have previously identified the system N transporter SN1 as being responsible for glutamine efflux from astroglia and proposed a system A transporter (SAT) in subsequent transport of glutamine into neurons for neurotransmitter regeneration. Here, we demonstrate that SAT2 expression is primarily confined to glutamatergic neurons in many brain regions with SAT2 being predominantly targeted to the somatodendritic compartments in these neurons. SAT2 containing dendrites accumulate high levels of glutamine. Upon electrical stimulation in vivo and depolarization in vitro, glutamine is readily converted to glutamate in activated dendritic subsegments, suggesting that glutamine sustains release of the excitatory neurotransmitter via exocytosis from dendrites. The system A inhibitor MeAIB (alpha-methylamino-iso-butyric acid) reduces neuronal uptake of glutamine with concomitant reduction in intracellular glutamate concentrations, indicating that SAT2-mediated glutamine uptake can be a prerequisite for the formation of glutamate. Furthermore, MeAIB inhibited retrograde signaling from pyramidal cells in layer 2/3 of the neocortex by suppressing inhibitory inputs from fast-spiking interneurons. In summary, we demonstrate that SAT2 maintains a key metabolic glutamine/glutamate balance underpinning retrograde signaling by dendritic release of the neurotransmitter glutamate.
authors.affiliation: The Biotechnology Centre of Oslo, University of Oslo, N-0317 Oslo, Norway.
authors.forename: Monica
authors.initials: M
authors.lastname: Jenstad
authors.forename: Abrar Z
authors.initials: AZ
authors.lastname: Quazi
authors.forename: Misha
authors.initials: M
authors.lastname: Zilberter
authors.forename: Camilla
authors.initials: C
authors.lastname: Haglerød
authors.forename: Paul
authors.initials: P
authors.lastname: Berghuis
authors.forename: Navida
authors.initials: N
authors.lastname: Saddique
authors.forename: Michel
authors.initials: M
authors.lastname: Goiny
authors.forename: Doungjai
authors.initials: D
authors.lastname: Buntup
authors.forename: Svend
authors.initials: S
authors.lastname: Davanger
authors.forename: Finn-Mogens
authors.initials: FM
authors.lastname: S Haug
authors.forename: Carol A
authors.initials: CA
authors.lastname: Barnes
authors.forename: Bruce L
authors.initials: BL
authors.lastname: McNaughton
authors.forename: Ole Petter
authors.initials: OP
authors.lastname: Ottersen
authors.forename: Jon
authors.initials: J
authors.lastname: Storm-Mathisen
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
authors.forename: Farrukh A
authors.initials: FA
authors.lastname: Chaudhry
mesh_terms: D026924:Amino Acid Transport System A / Q000276:immunology / Q000378:metabolism*; D026905:Amino Acid Transport Systems / Q000378:metabolism; D000818:Animals; D000918:Antibody Specificity; D002478:Cells, Cultured; D003712:Dendrites / Q000502:physiology*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D007124:Immunoenzyme Techniques; D008297:Male; D019579:Neocortex / Q000166:cytology / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D017966:Pyramidal Cells / Q000502:physiology / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D026924:Amino Acid Transport System A; D026905:Amino Acid Transport Systems; C486716:Slc38a1 protein, rat; C412568:Slc38a2 protein, rat; D005973:Glutamine; D015091:beta-Alanine; C012924:2,2-dimethyl-beta-alanine; D018698:Glutamic Acid