Altered expression of the glutamate transporter EAAT2b in neurological disease.
Functional studies suggest that up to 95% of all glutamate transport is handled by the glutamate transporter EAAT2. Amino and C-terminal antibodies demonstrate that under normal conditions EAAT2 is specific to astrocytes. A truncated splice variant of EAAT2, known as EAAT2b, also has been identified in astrocytes and some neurons. In vitro studies suggest EAAT2b transports glutamate similar to EAAT2, although the contribution of EAAT2b to normal clearance of extracellular glutamate is unknown. To investigate EAAT2b biology in pathological conditions, we examined the cellular and regional distribution of EAAT2b in amyotrophic lateral sclerosis. Using epitope-specific, affinity purified antibodies, we found that EAAT2b tissue levels were increased by more than twofold in amyotrophic lateral sclerosis motor cortex, whereas EAAT2 levels were decreased by up to 95%. EAAT2b distribution in normal human cortex was largely confined to the neuropil-like EAAT2, with occasional faint neuronal expression. In contrast, amyotrophic lateral sclerosis motor cortex had an obvious qualitative increase in neuropil EAAT2b staining and a drastic increase in neuronal soma and dendritic EAAT2b immunostaining. Despite these increases in EAAT2b immunostaining, functional transporter studies demonstrated a large loss of EAAT2 function. These studies clearly document altered regulation and splicing of the dominant glutamate transporter EAAT2 under conditions of neurological stress.
Maragakis
Nicholas J
NJ
Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Dykes-Hoberg
Margaret
M
Rothstein
Jeffrey D
JD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002460:Cell Line; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009422:Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051381:Rats
D027342:Excitatory Amino Acid Transporter 2