The Lurcher mutation identifies δ2 as an AMPA/kainate receptor-like channel that is potentiated by Ca2+

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(Lc) channels 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.