Deletion of the γ-aminobutyric acid transporter 2 (GAT2 and SLC6A13) gene in mice leads to changes in liver and brain taurine contents.
The GABA transporters (GAT1, GAT2, GAT3, and BGT1) have mostly been discussed in relation to their potential roles in controlling the action of transmitter GABA in the nervous system. We have generated the first mice lacking the GAT2 (slc6a13) gene. Deletion of GAT2 (both mRNA and protein) neither affected growth, fertility, nor life span under nonchallenging rearing conditions. Immunocytochemistry showed that the GAT2 protein was predominantly expressed in the plasma membranes of periportal hepatocytes and in the basolateral membranes of proximal tubules in the renal cortex. This was validated by processing tissue from wild-type and knockout mice in parallel. Deletion of GAT2 reduced liver taurine levels by 50%, without affecting the expression of the taurine transporter TAUT. These results suggest an important role for GAT2 in taurine uptake from portal blood into liver. In support of this notion, GAT2-transfected HEK293 cells transported [(3)H]taurine. Furthermore, most of the uptake of [(3)H]GABA by cultured rat hepatocytes was due to GAT2, and this uptake was inhibited by taurine. GAT2 was not detected in brain parenchyma proper, excluding a role in GABA inactivation. It was, however, expressed in the leptomeninges and in a subpopulation of brain blood vessels. Deletion of GAT2 increased brain taurine levels by 20%, suggesting a taurine-exporting role for GAT2 in the brain.
Centre of Molecular Biology and Neuroscience, Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
Yun
Y
Zhou
Centre of Molecular Biology and Neuroscience, Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
Silvia
S
Holmseth
HHMI, Janelia Farm Research Campus, Ashburn, Virginia 20147.
Caiying
C
Guo
Department for Neurohabilitation, Oslo University Hospital, N-0372 Oslo, Norway; Norwegian Defense Research Establishment, N-2027 Kjeller, Norway.
Bjørnar
B
Hassel
Department für Pharmazie, Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, D-81377 München, Germany.
Georg
G
Höfner
Department of Pathology, Oslo University Hospital, University of Oslo, N-0372 Oslo, Norway.
Henrik S
HS
Huitfeldt
Department für Pharmazie, Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, D-81377 München, Germany.
Klaus T
KT
Wanner
Centre of Molecular Biology and Neuroscience, Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway. Electronic address: n.c.danbolt@medisin.uio.no.
Niels C
NC
Danbolt
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D001923:Brain Chemistry; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007672:Kidney Cortex / Q000166:cytology / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013654:Taurine / Q000235:genetics / Q000378:metabolism*
D050485:GABA Plasma Membrane Transport Proteins; C490439:Slc6a12 protein, mouse; C493419:Slc6a13 protein, mouse; C092004:Slc6a13 protein, rat; D013654:Taurine