N-methyl-D-aspartate receptors (NMDARs): a glutamate-activated cation channel with biased signaling and therapeutic potential in brain disorders

Abstract

N-methyl-D-aspartate receptors (NMDARs) are a class of calcium-permeable ion channel that are extensively distributed throughout the body, composed of various subunits. The presence of diverse ligands and subcellular localizations of the receptors confers biased signaling and distinct functional roles. Activation of the NMDARs induces calcium influx, which plays a pivotal role in neurotransmitter release, synaptic plasticity, and intracellular signaling. Differential localization of NMDARs at synaptic and extrasynaptic sites results in divergent physiological effects; excessive or insufficient activation of NMDARs disrupts calcium homeostasis, leading to neuronal damage and subsequent neurological dysfunction as well as related diseases. Therefore, it is crucial to develop drugs targeting NMDARs with high efficacy and low toxicity for treating brain disorders associated with NMDARs abnormalities. In this review, we summarize both mechanism research and clinical studies on NMDARs while discussing potential therapeutic targets aimed at modulating ion channel activity through regulating mechanisms, subunit rearrangement, membrane expression, and the specific targeting of synaptic versus extrasynaptic NMDARs. Our aim is to provide new insights for innovative drug development.