Ultrastructure and ligand-gating of the human GluD1 receptor

The delta-type ionotropic glutamate receptors (iGluRs) GluD1 and GluD2 are ligand-gated ion channels that are fundamental for regulating both excitatory and inhibitory synapses. Rising evidence points to the role of GluD1 in the development of neurological diseases. However, the ultrastructure of human GluD1 (hGluD1) and the molecular basis for its ligand-gating remain unclear. Here, we define the ultrastructure of hGluD1 with cryo-electron microscopy (cryoEM) and through single channel bilayer recordings, show evidence of its ligand-gating capabilities. While hGluD1 exhibits a non-swapped architecture, it contains conserved iGluR moieties that enable ligand-gating, such as a ligand-binding domain (LBD) tethered to a transmembrane ion channel. Binding of the neurotransmitter γ-aminobutyric acid (GABA) or D-serine to the LBD enables cation influx through the hGluD1 ion channel in a concentration-dependent manner. Our findings delineate the molecular architecture and function of hGluD1, provide foundations for understanding patient mutations in hGluD1, and will invigorate therapeutic development against hGluD1.