Summary: A research team has identified a precise molecular “switch” that regulates NMDA receptors—central components of excitatory synaptic transmission—by preventing excessive synaptic activation. The study shows that MDGA2 and EphB2 compete to control receptor activation, with MDGA2 acting as a natural inhibitor of EphB2-driven NMDA receptor function.
Using AI-driven protein structure prediction, researchers mapped the binding interfaces between MDGA2 and EphB2 and confirmed the functional consequences in cellular experiments. These insights reveal how synaptic strength and signal duration are tuned and suggest new directions for targeted therapies in conditions such as autism spectrum disorder, where excitatory signaling is often altered.
Key Facts:
- Molecular brake: MDGA2 binds EphB2 and competitively inhibits EphB2-mediated activation of NMDA receptors, reducing excitatory signaling.
- AI-supported structural insight: The team used ColabFold to predict MDGA2–EphB2 binding sites and validated these predictions experimentally.
- Potential treatments: Modulating this pathway could guide precision therapies for autism and other disorders involving synaptic overactivity.
Source: DGIST
DGIST (President Kunwoo Lee) reports that a research team led by Professors Ko Jaewon and Um Ji Won at the Center for Synapse Diversity and Specificity (CSDS) in the Department of Brain Sciences has discovered a molecular mechanism that coordinates N-methyl-D-aspartate (NMDA) receptor function, a key regulator of excitatory synapses in the brain.
Synapses are the brain’s communication hubs, where neurons exchange information through precisely timed and scaled electrical and chemical signals. NMDA receptors are central to controlling both the intensity and duration of excitatory transmission; when their regulation is disrupted, signaling can become excessive or insufficient, with consequences for circuit function and behavior.
The DGIST team is the first to describe “switch proteins” that directly suppress NMDA receptor function and to explain how this suppression operates at the molecular level.
Central to the discovery is the interaction between MAM domain-containing glycosylphosphatidylinositol anchor protein 2 (MDGA2) and Ephrin type-B receptor 2 (EphB2). EphB2 is known to enhance NMDA receptor activity, but the team showed experimentally that MDGA2 interferes with that process by binding to EphB2 and preventing Ephrin-B1 from engaging the receptor.
To pinpoint contact points between MDGA2 and EphB2, the researchers used ColabFold, an AI-based protein structure prediction tool, to model the complex. From these models they identified critical amino acid residues at the interface and validated their functional roles in cultured neurons, demonstrating how MDGA2 binding dampens NMDA receptor-mediated synaptic responses.
DGIST CSDS has pursued the molecular regulation of synapses since 2011. Earlier work characterized MDGA proteins as inhibitors of synapse formation and function, first highlighted in 2013. In 2024, conditional knockout mouse studies showed that MDGA1 and MDGA2 reduce synapse number and impair neurotransmission, affecting inhibitory and excitatory synapses respectively.
The new findings build on that foundation by showing that MDGA2 specifically binds EphB2 to suppress NMDA receptor function, providing a mechanistic explanation for its role as an excitatory synapse regulator.
These results suggest a path toward precision therapies that can selectively modulate excitatory circuits. For disorders characterized by excessive synaptic excitation—such as some forms of autism spectrum disorder—drugs or biologics that mimic or enhance MDGA2 function might normalize synaptic activity with greater specificity and fewer side effects than broad-acting agents.
Professor Um Ji Won summarized: “This study confirms our previous model that the MDGA2 protein acts as a conductor that coordinates the function of excitatory synapses by interfering with key synaptic adhesion proteins that are structurally distinct.”
Professor Ko Jaewon added: “The MDGA2 protein is strongly associated with several neurodevelopmental disorders, including autism spectrum disorders. Proteins that interact with MDGA2, such as EphB2, are also relevant, and we plan to extend this work into preclinical studies.”
Dr. Kim Hyun-ho, a member of CSDS at DGIST, is first author of the study. The research was published online on May 1, 2025, in Progress in Neurobiology.
Funding: This work was supported by the Global Leader Research Program, the Basic Research Laboratory Support Program, the Mid-Career Researcher Support Program, and the Sejong Science Fellowship from the Ministry of Science and Information Communication Technology and the National Research Foundation of Korea.
About this neuroscience and autism research news
Author: Wankyu Lim
Source: DGIST
Contact: Wankyu Lim – DGIST
Image: The image is credited to Neuroscience News
Original Research: Open access.
“EphB2 receptor tyrosine kinase-mediated excitatory synaptic functions are negatively modulated by MDGA2” by Ko Jaewon et al. Progress in Neurobiology
Abstract
EphB2 receptor tyrosine kinase-mediated excitatory synaptic functions are negatively modulated by MDGA2
MDGA2 functions as an excitatory synapse-specific suppressor that uses distinct extracellular mechanisms to negatively regulate multiple postsynaptic properties. The study identifies EphB2, an excitatory synapse-specific receptor tyrosine kinase, as a binding partner of MDGA2.
The first three immunoglobulin-like domains of MDGA2 bind in cis to the ligand-binding domain of EphB2, allowing MDGA2 to compete with Ephrin-B1 for EphB2 interaction. In mouse brain tissue, EphB2 forms complexes with MDGA2 and GluN2B-containing NMDA receptors. Deletion of MDGA2 promotes formation of the EphB2–Ephrin-B1 complex but does not change surface expression levels or Ephrin-stimulated activation of EphB2 and downstream GluN2B-containing NMDA receptors in cultured neurons.
AlphaFold-based molecular replacement experiments indicate that MDGA2 binding to EphB2 is necessary to suppress spontaneous synaptic transmission and NMDA receptor–mediated (but not AMPA receptor–mediated) postsynaptic responses at excitatory synapses in cultured neurons. Together, these findings suggest MDGA2 is a versatile regulator that suppresses distinct excitatory postsynaptic properties through different transsynaptic pathways.