Abstract
Neurodegeneration in Lurcher (Lc) mice results from constitutive activation of delta 2, a subunit of ionotropic glutamate receptors (GluRs) with unknown natural ligands and channel properties. Homo-oligomeric channels of GluR- delta 2 with the Lurcher mutation (GluR- delta 2 super(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 Ca super(2+) was similar to 2-3%, comparable with that found in Ca super(2+)-permeable AMPA/kainate channels. Currents through GluR- delta 2 super(Lc) channels were also potentiated by extracellular Ca super(2+) in a biphasic manner, with maximal potentiation occurring at physiological concentrations of Ca super(2+). We examined the functional role of the Q/R site in GluR- delta 2 super(Lc) by replacing glutamine with arginine. Analogous to AMPA/kainate receptors, GluR- delta 2 super(Lc)(R) channels showed no voltage-dependent block by intracellular polyamines and were nominally impermeable to Ca super(2+). The potentiation by Ca super(2+), however, remained intact. Hence, GluR- delta 2 super(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 Ca super(2+) and a permeability to Ca super(2+) 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.