biostudies-literatureWang HNIGMS NIH HHS1063-1071https://www.ebi.ac.uk/biostudies/studies/S-EPMC12520249biostudies-literatureUnknown647(8091)Delta-type ionotropic glutamate receptors (iGluRs, also known as GluDs) are members of the iGluR ligand-gated ion channel family, yet their function remains unknown¹. Although GluDs are widely expressed in the brain, have key roles in synaptic organization, and harbour disease-linked mutations, whether they retain iGluR-like channel function is debated as currents have not been directly observed^2,3. Here we define GluDs as ligand-gated ion channels that are tightly regulated in cellular contexts by purifying human GluD2 (hGluD2) and directly characterizing its structure and function using cryo-electron microscopy and bilayer recordings. We show that hGluD2 is activated by D-serine and GABA (γ-aminobutyric acid), with augmented activation at physiological temperatures. We reveal that hGluD2 contains an ion channel directly coupled to clamshell-like ligand-binding domains, which are coordinated by the amino-terminal domain above the ion channel. Ligand binding triggers channel opening via an asymmetric mechanism, and a cerebellar ataxia point mutation in the ligand-binding domain rearranges the receptor architecture and induces leak currents. Our findings demonstrate that GluDs possess the intrinsic biophysical properties of ligand-gated ion channels, reconciling prior conflicting observations to establish a framework for understanding their cellular regulation and for developing therapies targeting GluD2.NatureDelta-type glutamate receptors are ligand-gated ion channels.PMC12520249R35 GM154904R35 GM122528Twomey ECMondal AKAhmed FKhau JWang HfalseDelta-type glutamate receptors are ligand-gated ion channels.Delta-type ionotropic glutamate receptors (iGluRs, also known as GluDs) are members of the iGluR ligand-gated ion channel family, yet their function remains unknown¹. Although GluDs are widely expressed in the brain, have key roles in synaptic organization, and harbour disease-linked mutations, whether they retain iGluR-like channel function is debated as currents have not been directly observed^2,3. Here we define GluDs as ligand-gated ion channels that are tightly regulated in cellular contexts by purifying human GluD2 (hGluD2) and directly characterizing its structure and function using cryo-electron microscopy and bilayer recordings. We show that hGluD2 is activated by D-serine and GABA (γ-aminobutyric acid), with augmented activation at physiological temperatures. We reveal that hGluD2 contains an ion channel directly coupled to clamshell-like ligand-binding domains, which are coordinated by the amino-terminal domain above the ion channel. Ligand binding triggers channel opening via an asymmetric mechanism, and a cerebellar ataxia point mutation in the ligand-binding domain rearranges the receptor architecture and induces leak currents. Our findings demonstrate that GluDs possess the intrinsic biophysical properties of ligand-gated ion channels, reconciling prior conflicting observations to establish a framework for understanding their cellular regulation and for developing therapies targeting GluD2.2025-01-01T00:00:00Z2025 Nov2026-06-11T05:03:43.375Z2026-06-11T03:07:57.557ZS-EPMC125202494095757910.1038/s41586-025-09610-x