Volatile anesthetics attenuate oxidative stress-reduced activity of glutamate transporter type 3.

Abstract

Volatile anesthetics enhance the activity of glutamate transporter Type 3 (also called excitatory amino acid transporter Type 3, EAAT3), the major neuronal EAAT. In addition to glutamate, EAAT3 can also uptake L-cysteine, the rate-limiting substrate for the synthesis of glutathione. Our previous study showed that oxidative stress inhibited glutamate-induced EAAT3 activity. We determined whether oxidative stress would reduce L-cysteine-induced EAAT3 activity and whether this reduction would be attenuated by volatile anesthetics. Rat EAAT3 was expressed in Xenopus oocytes. L-glutamate- and L-cysteine-induced membrane currents were recorded using the 2-electrode voltage clamp technique. The peak current was quantified to reflect the amount of transported substrates because transport of substrates via EAATs is electrogenic. Exposure of oocytes to 5 mM tert-butyl hydroperoxide, an organic oxidant, for 10 min reduced the V(max), but did not affect the K(m), of EAAT3 for L-cysteine. The volatile anesthetics isoflurane, sevoflurane, and desflurane at concentrations from 1% to 3% attenuated the tert-butyl hydroperoxide-reduced EAAT3 activity for L-glutamate and L-cysteine. Our results suggest that volatile anesthetics preserve EAAT3 function to transport L-glutamate and L-cysteine under oxidative stress, which may be a mechanism for the neuroprotective effects of volatile anesthetics.