Positive allosteric modulation of GluN1/GluN3 NMDA receptors

Author

Mia Ruth Johns, University of MontanaFollow

Year of Award

2025

Document Type

Professional Paper

Degree Type

Master of Science (MS)

Other Degree Name/Area of Focus

Neuroscience

Department or School/College

Molecular and Biomedical Sciences

Committee Chair

Kasper Hansen

Committee Co-chair

Sarah Certel

Commitee Members

Kasper Hansen, Andrew Rau, Katie Holick

Keywords

Neuroscience, ion channel, drug discovery, neuropharmacology, positive modulation

Subject Categories

Biochemistry, Biophysics, and Structural Biology | Neuroscience and Neurobiology | Pharmacy and Pharmaceutical Sciences

Abstract

N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission in the central nervous system (CNS) where they play critical roles in normal and pathological brain functions and neurodevelopment. While the glutamate/glycineactivated GluN2-containing NMDA receptors (GluN1/GluN2) have been extensively studied, the physiological roles and pharmacology of glycine-activated GluN3-containing receptors (GluN1/GluN3) remain less understood. Although GluN1/GluN3 receptors exhibit unique functional properties and play distinct roles in neuronal development and synapse maturation, studies of their precise roles in neurophysiology and circuit function are impeded by limited availability of GluN3-selective pharmacological tools. This study describes UCM-A86, a novel GluN3-selective positive allosteric modulator, with EC₅₀ values of 18 µM and 20 µM at GluN1/GluN3A and GluN1/GluN3B receptors, respectively. UCM-A86 selectively potentiates recombinant GluN1/GluN3A and GluN1/GluN3B receptors by 431% and 155%, respectively, relative to activation by glycine, with no activity at recombinant GluN1/GluN2A-D receptors. Furthermore, UCM-A86 selectively potentiates responses from native GluN1/GluN3A receptors expressed in somatostatin-expressing interneurons of the somatosensory cortex with no modulation of hippocampal AMPA receptor- and GluN1/2 NMDA receptor-mediated excitatory postsynaptic currents. Mechanistic studies suggest that UCM-A86 modulation is facilitated by agonist binding (or channel gating) and that UCM-A86 primarily potentiates GluN1/GluN3A by increasing open probability with no effects on mean channel conductance. These findings advance the synthetic pharmacology of GluN1/GluN3 receptors and provide a novel tool for modulation of native GluN3-containing NMDA receptors.

Recommended Citation

Johns, Mia Ruth, "Positive allosteric modulation of GluN1/GluN3 NMDA receptors" (2025). Graduate Student Theses, Dissertations, & Professional Papers. 12538.
https://scholarworks.umt.edu/etd/12538