Glutamate ionotropic receptor NMDA type subunit 1 (GluN1) (GluN1)

The GluN1 subunit of the N-methyl-D-aspartate (NMDA) receptor is an essential component of the heterotetrameric NMDAR complex, which mediates excitatory neurotransmission and synaptic plasticity in the central nervous system (UniProt: P35486). A specific epitope within the N-terminal domain (NTD) of GluN1 serves as a binding site for tissue-type plasminogen activator (tPA), a serine protease that acts as both an endogenous signaling molecule and a clinical thrombolytic agent (Vivien et al., 2004). When tPA binds to this GluN1 epitope, it enhances NMDAR signaling, which can lead to excessive calcium influx and neuronal death (excitotoxicity), particularly during ischemic stroke or traumatic brain injury (Macrez et al., 2016). Therapeutic strategies, such as the monoclonal antibody Glunomab, specifically target this tPA-binding epitope to decouple the neurotoxic effects of tPA from its beneficial thrombolytic activity. This approach aims to provide neuroprotection without interfering with the basal physiological functions of the NMDA receptor, addressing a major limitation of broad-spectrum NMDAR antagonists. Research indicates that blocking this specific interaction can reduce infarct volume and improve neurological outcomes in animal models of stroke. The target is particularly relevant because tPA is the only FDA-approved pharmacological treatment for acute ischemic stroke, yet its neurotoxic side effects limit its safety profile. By targeting the GluN1 NTD epitope, clinicians may be able to administer tPA more safely or develop adjunct therapies that mitigate its risks.

Other names

GRIN1NMDA receptor subunit 1NR1Glutamate [NMDA] receptor subunit zeta-1NMDAR1tPA-binding site of GluN1

Glunomab is a monoclonal antibody that binds to the N-terminal domain of the GluN1 subunit, specifically blocking the interaction between tissue-type plasminogen activator (tPA) and the NMDA receptor. This prevents tPA-induced potentiation of NMDAR activity and subsequent excitotoxic neuronal death during stroke (Macrez et al., 2016).