{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Wang H"],"funding":["NIGMS NIH HHS"],"pagination":["1063-1071"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12520249"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["647(8091)"],"pubmed_abstract":["Delta-type ionotropic glutamate receptors (iGluRs, also known as GluDs) are members of the iGluR ligand-gated ion channel family, yet their function remains unknown<sup>1</sup>. 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<sup>2,3</sup>. 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."],"journal":["Nature"],"pubmed_title":["Delta-type glutamate receptors are ligand-gated ion channels."],"pmcid":["PMC12520249"],"funding_grant_id":["R35 GM154904","R35 GM122528"],"pubmed_authors":["Twomey EC","Mondal AK","Ahmed F","Khau J","Wang H"],"additional_accession":[]},"is_claimable":false,"name":"Delta-type glutamate receptors are ligand-gated ion channels.","description":"Delta-type ionotropic glutamate receptors (iGluRs, also known as GluDs) are members of the iGluR ligand-gated ion channel family, yet their function remains unknown<sup>1</sup>. 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<sup>2,3</sup>. 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.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Nov","modification":"2026-06-11T05:03:43.375Z","creation":"2026-06-11T03:07:57.557Z"},"accession":"S-EPMC12520249","cross_references":{"pubmed":["40957579"],"doi":["10.1038/s41586-025-09610-x"]}}