The NR2B-specific interactions of polyamines and protons with the N-methyl-D-aspartate receptor

Many compounds exhibit NR2B-specific modulation of the N-methyl-D-aspartate receptor, although their mechanism(s) of action are largely unknown. Using chimeric NR2A/NR2B subunits, we have located a region of NR2B (amino acids 138-238) which regulated glycine-independent polyamine stimulation. Mutation of glutamate 201 in this region affected stimulation by polyamines in the order E201D < E201A < E201N < E201R. The relief of proton inhibition of the N-methyl-D-aspartate-induced currents mediated by these mutant receptors correlated with the reduction in glycine-independent polyamine stimulation. Electrophysiological evidence with a triple mutant of NR2A further supports the hypothesis that polyamine stimulation may be linked to the relief of tonic inhibition by protons and demonstrates the crucial role of amino acids 200 and 201 in polyamine stimulation. Polyamines and protons, therefore, share common NR2B determinants.