Computational studies of NMDA receptors: differential effects of neuronal activity on efficacy of competitive and non-competitive antagonists

N-Methyl-D-Aspartate receptors (NMDARs) play important physiological as well as pathological roles in the central nervous system (CNS). While NMDAR competitive antagonists, such as D-2-Amino-5-Phosphopentanoic acid (AP5) have been shown to impair learning and memory, the non-competitive antagonist, memantine, is paradoxically beneficial in mild to moderate Alzheimer's disease (AD) patients. It has been proposed that differences in kinetic properties could account for antagonist functional differences. Here we present a new elaborated kinetic model of NMDARs that incorporates binding sites for the agonist (glutamate) and co-agonist (glycine), channel blockers, such as memantine and magnesium (Mg(2+)), as well as competitive antagonists. We first validated and optimized the parameters used in the model by comparing simulated results with a wide range of experimental data from the literature. We then evaluated the effects of stimulation frequency and membrane potential (Vm) on the characteristics of AP5 and memantine inhibition of NMDARs. Our results indicated that the inhibitory effects of AP5 were independent of Vm but decreased with increasing stimulation frequency. In contrast, memantine inhibitory effects decreased with both increasing Vm and stimulation frequency. They support the idea that memantine could provide tonic blockade of NMDARs under basal stimulation conditions without blocking their activation during learning. Moreover they underline the necessity of considering receptor kinetics and the value of the biosimulation approach to better understand mechanisms of drug action and to identify new ways of regulating receptor function.