Delta glutamate receptors are functional glycine- and ᴅ-serine-gated cation channels in situ.

Delta receptors are members of the ionotropic glutamate receptor superfamily and form trans-synaptic connections by interacting with the extracellular scaffolding protein cerebellin-1 and presynaptic transmembrane protein neurexin-1β. Unlike other family members, however, direct agonist-gated ion channel activity has not been recorded in delta receptors. Here, we show that the GluD2 subtype of delta receptor forms cation-selective channels when bound to cerebellin-1 and neurexin-1β. Using fluorescence lifetime measurements and chemical cross-linking, we reveal that tight packing of the amino-terminal domains of GluD2 permits glycine- and d-serine–induced channel openings. Thus, cerebellin-1 and neurexin-1β act as biological cross-linkers to stabilize the extracellular domains of GluD2 receptors, allowing them to function as ionotropic excitatory neurotransmitter receptors in synapses.