Delta-type glutamate receptors are ligand-gated ion channels

"Delta-type ionotropic glutamate receptors (iGluRs), or GluDs, are members of the iGluR ligand-gated ion channel family, yet their function remains enigmatic1. Although GluDs are widely expressed in the brain, play key roles in synaptic organization, and harbor disease-linked mutations, whether they retain iGluR-like channel function is debated as currents have not been directly observed2,3. 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"

"We show that hGluD2 is activated by D-serine and -aminobutyric acid (GABA), with augmented activation at physiological temperatures. We reveal that hGluD2 contains an ion channel directly coupled to clamshell-like ligand-binding domains (LBDs), which are coordinated by the amino terminal domain (ATD) above the ion channel. Ligand binding triggers channel opening via an asymmetric mechanism, and a cerebellar ataxia point mutation in the LBD rearranges the receptor architecture and induces leak currents."

Human GluD2 (hGluD2) is purified and directly characterized structurally and functionally using cryo-electron microscopy and bilayer recordings. hGluD2 is activated by D‑serine and GABA, with stronger activation at physiological temperatures. The receptor contains an ion channel directly coupled to clamshell-like ligand-binding domains coordinated by an amino-terminal domain above the pore. Ligand binding produces channel opening through an asymmetric mechanism. A cerebellar ataxia point mutation within the LBD alters receptor architecture and generates leak currents. GluDs therefore possess intrinsic ligand-gated ion channel biophysics, supporting frameworks for cellular regulation and therapeutic targeting of GluD2.

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