GluRdelta2 is a member of the iGluR family, but despite a prominent role in cerebellar synaptic plasticity, this receptor does not appear to function as an ion channel. Endogenous ligands that modulate the activity of native GluRdelta2 in the cerebellum have not been identified, but two candidate modulators are d-serine and extracellular calcium. Taking advantage of known crystal structures and spontaneously active GluRdelta2 receptors containing the lurcher mutation (GluRdelta2(Lc)), we investigated the mechanism by which calcium and d-serine regulate the activity of GluRdelta2(Lc). Our data suggest that calcium binding stabilizes the dimer interface formed between two agonist-binding domains and increases GluRdelta2(Lc) currents. The data further suggest that d-serine binding induces rearrangements at the dimer interface to diminish GluRdelta2(Lc) currents by a mechanism that resembles desensitization at AMPA and kainate receptors. Thus, we propose that calcium and d-serine binding have opposing effects on the stability of the dimer interface. Furthermore, the effects of calcium are observed at concentrations that are within the physiological range, suggesting that the ability of native GluRdelta2 to respond to ligand binding may be modulated by extracellular calcium. These findings place GluRdelta2 among AMPA and kainate receptors, where the dimer interface is not only a biologically important site for functional regulation, but also an important target for exogenous and endogenous ligands that modulate receptor function.