Manganese disrupts astrocyte glutamine transporter expression and function.
Glutamine (Gln) plays an important role in brain energy metabolism and as a precursor for the synthesis of neurotransmitter glutamate and GABA. Previous studies have shown that astrocytic Gln transport is impaired following manganese (Mn) exposure. The present studies were performed to identify the transport routes and the respective Gln transporters contributing to the impairment. Rat neonatal cortical primary astrocytes treated with Mn displayed a significant decrease in Gln uptake mediated by the principle Gln transporting systems, N and ASC. Moreover, systems N, ASC and L were less efficient in Gln export after Mn treatment. Mn treatment caused a significant reduction of both in mRNA expression and protein levels of SNAT3 (system N), SNAT2 (system A) and LAT2 (system L), and lowered the protein but not mRNA expression of ASCT2 (system ASC). Mn exposure did not affect the expression of the less abundant systems N transporter SNAT5 and the system L transporter LAT1, at either the mRNA or protein level. Hence, Mn-induced decrease of inward and outward Gln transport can be largely ascribed to the loss of the specific Gln transporters. Consequently, deregulation of glutamate homeostasis and its diminished availability to neurons may lead to impairment in glutamatergic neurotransmission, a phenomenon characteristic of Mn-induced neurotoxicity.
Sidoryk-Wegrzynowicz
Marta
M
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Lee
Eunsook
E
Albrecht
Jan
J
Aschner
Michael
M
D026962:Amino Acid Transport System ASC / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002712:Chlorides / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000502:physiology*; D017895:Manganese Compounds; D015778:Minor Histocompatibility Antigens; D051381:Rats; D017207:Rats, Sprague-Dawley
D026962:Amino Acid Transport System ASC; D026921:Amino Acid Transport Systems, Neutral; D002352:Carrier Proteins; D002712:Chlorides; D017895:Manganese Compounds; D015778:Minor Histocompatibility Antigens; C498849:Slc1a5 protein, rat; C037853:glutamine transport proteins; C403222:system N protein 1; C025340:manganese chloride