ALLOSTERIC MODULATION OF THE NMDA RECEPTOR BY DIHYDROLIPOIC AND LIPOIC ACID IN RAT CORTICAL-NEURONS IN-VITRO

The mitochondrial cofactor dihydrolipoic acid (DHLA) was observed to p otentiate N-methyl-D-aspartate (NMDA), but not non-NMDA, receptor-medi ated whole-cell responses in cultured neurons. This potentiation was r eadily reversed by the oxidizing agent 5,5'-dithio-bis-(2-nitro-benzoi c acid) (DTNB). DHLA was unable to increase NMDA responses previously potentiated by dithiothreitol, nor did it have an effect on NMDA recep tors alkylated with N-ethylmaleimide. Single-channel recordings reveal ed that DHLA produced an increase in NMDA channel open frequency, with no change in single-channel conductance or open time. In contrast, li poic acid reversed the potentiation of NMDA-evoked responses produced by dithiothreitol and had no effect on NMDA receptors previously oxidi zed by DTNB. DHLA and lipoic acid are pervasively found substances tha t readily permeate cellular membranes and thus may influence NMDA rece ptor activity in vivo by modifying its redox site.