Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Monday Speaker Abstracts

REPRESENTATION AND DESIGN IN NETWORK MODELS OF CATEGORY DEFICITS Andrei Ionu ţ M ă r ăş oiu University of Bucharest, Romania No Abstract

SUBTYPE-SPECIFIC CONFORMATIONAL LANDSCAPES GOVERN NMDA RECEPTOR GATING Vasanthi Jayaraman University of Texas Health Science Center at Houston, USA N-methyl-D-aspartate (NMDA) receptors are glutamate- and glycine-gated ion channels that are essential for excitatory neurotransmission, synaptic plasticity, and excitotoxic neuronal injury. Although receptor activation is tightly regulated by co-agonists and modulators, the conformational transitions that give rise to subtype-specific gating and functional diversity remain incompletely understood. Here, we used single-molecule Förster resonance energy transfer (smFRET) to define the conformational landscapes and dynamic transitions of multiple NMDA receptor subtypes, revealing common structural principles that govern activation across distinct GluN1 partner subunits. Across GluN1-containing receptors assembled with GluN2A, GluN2D, or GluN3 subunits, smFRET measurements spanning the amino-terminal domain, ligand-binding domain, and transmembrane domain uncovered subtype-dependent yet mechanistically convergent patterns of domain organization. Receptors with lower open probability preferentially occupied splayed, dynamic extracellular conformations that were associated with more constrained pore configurations, whereas higher open probability states correlated with compact extracellular arrangements and enhanced pore dynamics. Ligands and modulators shifted these equilibria in a consistent manner: agonists or potentiating conditions promoted tighter extracellular domain coupling and coordinated rearrangements in the transmembrane domain consistent with channel opening, while other ligand conditions favored extracellular decoupling and reduced activity. These observations support a unifying “bunch of flowers” model in which coordinated tightening of extracellular domains is coupled to widening of the channel gate to drive activation. Rather than acting through entirely distinct mechanisms, different subunits and modulatory conditions tune receptor function by reshaping a shared conformational landscape. This framework explains how diverse GluN1 partner subunits generate markedly different levels of activity, desensitization, and agonist potency, and provides mechanistic insight into NMDA receptor modulation.

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