Abstract
N-methyl-D-aspartate (NMDA) receptors mediate excitatory synaptic transmission in central nervous system and play important roles in development and synaptic plasticity, but have also been found to mediate neurotoxicity. Recently, 2-naphthoic acid (NPA) and its derivatives have been identified as allosteric, noncompetitive NMDA receptors inhibitors. The inhibitory selectivity of NPA derivatives among NMDA receptor subtypes was mapped to the ligand-binding domain (LBD), and the binding site of NPA is proposed to be located in the LBD dimer interface. However, the mechanism by which NPA exerts inhibitory effect is still unclear. We examined how NPA affects the gating reaction of NMDA receptors. Whole-cell patch clamp on HEK 293 cells expressing recombinant NR1-1a/NR2A showed that NPA has 90% maximum inhibition with IC50 of 2.1 mM. Furthermore, by recording single-channel currents from NR1-1a/NR2A receptors with 4 mM NPA, we found a 62% decrease in open probability (Po), due to a 2.5-fold decrease in mean open time (MOT) and a 2-fold increase in mean closed time (MCT). Kinetic modeling suggests NPA increases energy barrier of gating and destabilizes the open state, thus making NRs accumulate in the closed states along the activation pathway. These results provide insight into the inhibitory mechanism of NPA, and help anticipate its effects on both physiological and pathological conditions.
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