SUBUNIT-SPECIFIC INTERACTIONS OF CYANIDE WITH THE N-METHYL-D-ASPARTATE RECEPTOR

Cyanide can potentiate N-methyl-D-aspartate receptor-mediated physiolo gical responses in neurons. Here we show that this phenomenon may be a ttributable to a subunit-specific chemical modification of the recepto r directly by the toxin. N-Methyl-D-aspartate (30 mu M)-induced whole cell responses in mature (22-29 days in vitro) rat cortical neurons we re potentiated nearly a-fold by a 3-5-min treatment with 2 mM potassiu m cyanide, as did a similar treatment with 4 mM dithiothreitol. A 1-mi n incubation with the thiol oxidant 5,5'-dithio-bis(a-nitrobenzoic aci d) (0.5 mM) readily reversed the potentiation induced by either cyanid e or dithiothreitol. Cyanide did not increase further currents previou sly potentiated by dithiothreitol nor was it able to potentiate respon ses during brief co-application with the agonist. Transient expression studies in Chinese hamster ovary cells with wild-type and mutated rec ombinant N-methyl-D-aspartate subunits (NR) demonstrated that cyanide selectively potentiated NR1/NR2A receptors, presumably via the chemica l reduction of NR2A. In contrast, currents mediated by NR1/NR2B recept ors were somewhat diminished by the metabolic inhibitor. Some of the e ffects of cyanide on NR1/NR2B receptors may be mediated by the formati on of a thiocyanate adduct with a cysteine residue located in NR1. Cya nide thus is able to distinguish chemically between two different N-me thyl-D-aspartate receptor subtypes and produce diametrically opposing functional effects.