Release of L-aspartate by reversal of glutamate transporters.
Aspartate is released in the brain during metabolic inhibition and can activate NMDA receptors. We compared the characteristics of aspartate and glutamate release mediated by reversed operation of GLAST glutamate transporters in salamander retinal glial cells, when high [K(+)](o) solution was applied to mimic the ionic conditions of stroke or glaucoma. In the absence of Cl(-), to isolate the transport-associated current of the transporters, reversed uptake of aspartate and glutamate had similar characteristics. Both were increased strongly by depolarisation, inhibited by the transport inhibitor TBOA (DL-threo-beta-benzyloxyaspartate), and activated in a first order manner by intracellular amino acid (in the presence of 20mM [Na(+)](i)) with an EC(50) of 0.8mM for aspartate and 2.3mM for glutamate. In stroke the extracellular pH shifts acid by around a pH unit: this reduced the release of aspartate and glutamate by reversed uptake by a factor of 8-20. The external Cl(-) concentration had only a small effect on the current associated with reversed uptake of aspartate and glutamate. Tamoxifen, which reduces amino acid release through swelling-activated anion channels in glial cells, was found to inhibit reversed uptake with an IC(50) which was >100 microM. Part of the activation of NMDA receptors which occurs in ischaemia is likely to reflect the release of aspartate by reversed uptake.
Marcaggi
Païkan
P
Department of Physiology, University College London, Gower Street, London, WC1E 6BT, UK.
Hirji
Nashila
N
Attwell
David
D
D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018698:Glutamic Acid / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D012160:Retina / Q000166:cytology; D014562:Caudata
D027322:Amino Acid Transport System X-AG; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; D011188:Potassium