The Lurcher mutation identifies delta 2 as an AMPA/kainate receptor-like channel that is potentiated by Ca(2+).
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-delta2 with the Lurcher mutation (GluR-delta 2(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 approximately 2-3%, comparable with that found in Ca(2+)-permeable AMPA/kainate channels. Currents through GluR-delta 2(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-delta 2(Lc) by replacing glutamine with arginine. Analogous to AMPA/kainate receptors, GluR-delta 2(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-delta 2(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.
Wollmuth
L P
LP
Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, New York 11794-5230, USA. lwollmuth@notes1.cc.sunysb.edu
Kuner
T
T
Jatzke
C
C
Seeburg
P H
PH
Heintz
N
N
Zuo
J
J
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D017470:Receptors, Glutamate / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
D018091:Receptors, AMPA; D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2; D002118:Calcium