FUNCTIONAL AND PHARMACOLOGICAL CHARACTERIZATION OF GLUN3-CONTAINING NMDA RECEPTORS

N-methyl-D-aspartate (NMDA) receptors are a member of ionotropic glutamate receptors that mediate excitatory neurotransmission across the mammalian central nervous system. NMDA receptors are organized into heterotetrameric assemblies containing two obligatory GluN1 subunits and two GluN2A-D, or GluN3A-B subunits. GluN1 and GluN3A-B bind glycine or D-serine, whereas GluN2A-D bind glutamate. The structural, functional, and pharmacological investigation of GluN1/3 NMDA receptors has been greatly hindered by their unconventional properties such as impermeability to Ca2+, insensitivity to the voltage-dependent block by Mg2+, and robust desensitization upon binding their endogenous agonist glycine. Another major barrier in GluN3 research has been the lack of selective and potent ligands. This dissertation presents new understanding to facilitate functional investigation of GluN3A-containing NMDA receptors, and provides a mechanistic and pharmacological roadmap for the development of selective and potent tool-compounds and therapeutics targeting GluN1/3 NMDA receptors