System A transporter SAT2 mediates replenishment of dendritic glutamate pools controlling retrograde signaling by glutamate.
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.
Jenstad
Monica
M
The Biotechnology Centre of Oslo, University of Oslo, N-0317 Oslo, Norway.
Quazi
Abrar Z
AZ
Zilberter
Misha
M
Haglerød
Camilla
C
Berghuis
Paul
P
Saddique
Navida
N
Goiny
Michel
M
Buntup
Doungjai
D
Davanger
Svend
S
S Haug
Finn-Mogens
FM
Barnes
Carol A
CA
McNaughton
Bruce L
BL
Ottersen
Ole Petter
OP
Storm-Mathisen
Jon
J
Harkany
Tibor
T
Chaudhry
Farrukh A
FA
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
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