AN ACTIVE-SITE HISTIDINE OF NR1 2C MEDIATES VOLTAGE-INDEPENDENT INHIBITION BY ZINC/

Endogenous zinc is an important modulator of ion channels of the centr al nervous system. To understand mechanisms of zinc inhibition, cloned heteromeric N-methyl-D-aspartate receptors (primary subunit NR1 with secondary subunits NR2A, NR2C or NR2D) were expressed in Xenopus oocyt es and studied under two-electrode voltage-clamp. Voltage-independent inhibition of NR1/2A heteromers by nanomolar concentrations of extrace llular zinc was observed in barium-containing perfusion solutions. In contrast, voltage-independent zinc inhibition of NR1/2C heteromers occ urred with lower affinity. Zinc inhibition data from NR1/2D heteromers was fit well with a voltage-independent one-site model and resembled that previously reported for NR1/2B. Reduction of zinc inhibition of N R1/2C heteromers was seen after labeling with the histidine-modifying reagent diethylpyrocarbonate. This finding suggests that the NR1/2C he teromeric ion channel contains an active-site histidine responsible fo r zinc inhibition. (C) 1997 Elsevier Science B.V.