Regulation of N-methyl-D-aspartate receptors by spermine and ifenprodil

Abstract

N -Methyl-D-aspartate (NMDA) receptors are a subtype of glutamate receptor. They are tetramers containing combinations of GluN1, GluN2, and GluN3 subunits. Activation of NMDA receptors is associated with the induction of synaptic plasticity including long-term potentiation and depression, processes that may underlie learning and memory. Excessive activation of NMDA receptors is also involved in neurodegeneration. Spermine has multiple effects on NMDA receptors, including stimulation and a weak voltage-dependent channel block; these effects involve binding of spermine to at least two distinct sites. Ifenprodil is an atypical NMDA receptor antagonist that selectively inhibits receptors containing the GluN2B subunit. Modeling the binding sites for spermine and ifenprodil on the regulatory (R) domains of NMDA receptor GluN1 and GluN2B subunits was carried out after measuring spermine stimulation and ifenprodil inhibition at receptors containing GluN1 and GluN2B R domain mutants. The modeling suggests that a space between the two R1 lobes of GluN1R and GluN2BR is promoted through binding of spermine, and that R1 lobes of GluN1R and GluN2BR come closer after binding of ifenprodil, an effect opposite to that seen after binding of spermine. The spermine-binding site involved in the channel block was also localized at the pore-forming and vestibule regions of NMDA receptors.