Abstract

Neurodegeneration in Lurcher (Lc) mice results from constitutive activation of δ2, a subunit of ionotropic glutamate receptors (GluRs) with unknown natural ligands and channel properties. Homo-oligomeric channels of GluR-δ2 with the Lurcher mutation (GluR-δ2^Lc) expressed in human embryonic kidney 293 cells showed a doubly rectifying current–voltage relation reminiscent of the block by intracellular polyamines in AMPA/kainate channels. Similarly, the fraction of the total current carried by Ca²⁺ was ∼2–3%, comparable with that found in Ca²⁺-permeable AMPA/kainate channels. Currents through GluR-δ2^Lc channels were also potentiated by extracellular Ca²⁺ in a biphasic manner, with maximal potentiation occurring at physiological concentrations of Ca²⁺. We examined the functional role of the Q/R site in GluR-δ2^Lc by replacing glutamine with arginine. Analogous to AMPA/kainate receptors, GluR-δ2^Lc(R) channels showed no voltage-dependent block by intracellular polyamines and were nominally impermeable to Ca²⁺. The potentiation by Ca²⁺, however, remained intact. Hence, GluR-δ2^Lcchannels are functionally similar to the AMPA/kainate receptor channels, consistent with the high-sequence identity shared by these subunits within the channel-lining M2 and M3 segments. Furthermore, potentiation by Ca²⁺ and a permeability to Ca²⁺ comparable with that of AMPA/kainate receptors provide a possible cause for cell death in Lurcher mice and may contribute to cerebellar long-term depression under physiological conditions.