Disease relevance of SLC1A6

• In the present report, we demonstrate the different expression of EAAT4 and GLAST in the pathologic condition, neonatal subarachnoid hemorrhage [1].
• Indeed, the correspondence between the absence of aldolase C and EAAT4 to sensitivity to ischemia could be demonstrated for zones of Purkinje cells as small as two neurons [2].
• Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus [2].
• After global brain ischemia, we found that Purkinje cells with low EAAT4 expression were selectively lost after cardiac arrest in GLAST mutant mice. This result demonstrates that GLAST plays a role in preventing excitotoxic cerebellar damage after ischemia in concert with EAAT4 [3].

High impact information on SLC1A6

• Cell culture studies demonstrate that wild-type but not mutant beta-III spectrin stabilizes EAAT4 at the plasma membrane [4].
• Studies of EAAT4 and EAAC1 indicate an extrasynaptic localization on perisynaptic membranes that are near release sites [5].
• Here we report the identification and characterization of two proteins, GTRAP41 and GTRAP48 (for glutamate transporter EAAT4 associated protein) that specifically interact with the intracellular carboxy-terminal domain of EAAT4 and modulate its glutamate transport activity [5].
• Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins [5].
• The transport activity encoded by EAAT4 has high apparent affinity for L-aspartate and L-glutamate, and has a pharmacological profile consistent with previously described cerebellar transport activities [6].
• EAAT4 controls activation of postsynaptic metabotropic glutamate receptors and influence cerebellar long-term depression [7].
• Regional differences in EAAT4 expression affect the degree of metabotropic glutamate receptor activation and therefore regulate synaptic plasticity [8]

Chemical compound and disease context of SLC1A6

• Although Bergmann's glia removes glutamate from the extracellular space surrounding Purkinje cells in the early stage of hypoxic-ischemic brain damage, the reaction of EAAT4 and GLAST in the cerebellar cortex under the subarachnoid hemorrhage was decreased, and immature glia had a delayed reaction [1].

Biological context of SLC1A6

• The activation process depends on both membrane potential and extracellular glutamate concentration and causes an accumulation of EAAT4 anion channels in a state favoring cation influx and anion efflux [9].
• At steady state, EAAT4 was activated by glutamate and Na+ with high affinities of 0.6 microM and 8.4 mM, respectively, and showed kinetics consistent with sequential binding of Na(+)-glutamate-Na+ [10].
• Finally, we examined whether glutamate signaling mediated by EAAT4 can modulate rod outer segment phagocytosis by the retinal pigment epithelium [11].
• Neither tamoxifen, known to inhibit both proliferation and glutamate uptake in RPE cells, nor retinoic acid nor insulin, also known to affect cell proliferation rates, were capable of changing the total levels of EAAT4 in APRE-19 cells [12].
• Facilitated activation of metabotropic glutamate receptors in cerebellar Purkinje cells in glutamate transporter EAAT4-deficient mice [13].
• The main role of EAAT4 is to remove low concentrations of glutamate that escape from the uptake by glial transporters at late times and thus prevents the transmitter from spilling over to neighboring synapses [14].

Anatomical context of SLC1A6

• In Xenopus oocytes expressing EAAT4, L-aspartate and L-glutamate elicited a current predominantly carried by chloride ions [6].
• Beta-III spectrin is highly expressed in Purkinje cells and has been shown to stabilize the glutamate transporter EAAT4 at the surface of the plasma membrane [4].
• In addition, the EAAT4-associated protein, GTRAP41, was found in the human, mouse, and squirrel retinas as well as in the rod outer segment preparation [11].
• The dendrites and cell bodies of Purkinje cells, which showed EAAT4 immunoreactivity, were ensheathed by GLAST processes [15].
• Immunohistochemistry revealed that EAAT4 was localized in rod and cone photoreceptor outer segments in the human retina, and in the outer and inner segments of mouse and ground squirrel retinas [11].

Associations of SLC1A6 with chemical compounds

• Thus EAAT4 combines the re-uptake of neurotransmitter with a mechanism for increasing chloride permeability, both of which could regulate excitatory neurotransmission [6].
• Thus, enhancement of the substrate-gated currents in EAAT4 does not correlate with the rate of substrate transport and suggests that the niflumic acid-induced currents are not thermodynamically coupled to the transport of substrate [16].
• 3. Niflumic acid and arachidonic acid co-applied with substrate to EAAT4-expressing oocytes had similar functional consequences [16].
• In this study we demonstrate that Zn(2+) ions inhibit the uncoupled anion conductance and also reduce the affinity of L-aspartate for EAAT4 [17].
• Two histidine residues in the extracellular loop between transmembrane domains three and four of EAAT4 appear to confer Zn(2+) inhibition of the anion conductance [17].

Other interactions of SLC1A6

• With the exception of EAAT4, the glutamate transporter/chloride channel situated on GABAergic Purkinje cells in the cerebellum, the functions of somatodendritic heterocarriers is not understood [18].
• We also detected decreased EAAT3 transcript expression in schizophrenia and decreased EAAT4 transcript expression in major depressive disorder [19].
• In preterm infants with subarachnoid hemorrhage the decrease in EAAT4 immunoreactivity was more prominent than in term infants, and GLAST immunoreactivity in the inner granular cell layer decreased and reappeared later than in term infants with subarachnoid hemorrhage [1].

Analytical, diagnostic and therapeutic context of SLC1A6

• Further immunocytochemical and co-immunoprecipitation experiments demonstrated that GTRAP41 was colocalized and interacted in vivo with EAAT4 [11].
• Immunoblotting studies showed the presence of EAAT4-immunoreactive proteins in human and mouse retinas, corresponding to EAAT4 monomers and dimers [11].
• The astrocytic localization of EAAT4 was further confirmed in astrocyte cultures by double-labeled fluorescent immunocytochemistry and Western blotting [20].
• Reverse transcriptase-polymerase chain reaction analysis demonstrated mRNA expression of EAAT4 in astrocyte cultures [20].

References