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 Ca
2+
was ∼2–3%, comparable with that found in Ca
2+
-permeable AMPA/kainate channels. Currents through GluR-δ2
Lc
channels were also potentiated by extracellular Ca
2+
in a biphasic manner, with maximal potentiation occurring at physiological concentrations of Ca
2+
. 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 Ca
2+
. The potentiation by Ca
2+
, 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 Ca
2+
and a permeability to Ca
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.