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The Journal of Neuroscience, August 15, 2000, 20(16):5973-5980
The Lurcher Mutation Identifies  2 as an AMPA/Kainate
Receptor-Like Channel That Is Potentiated by Ca2+
Lonnie P.
Wollmuth1,
Thomas
Kuner2, 3,
Claudia
Jatzke1,
Peter H.
Seeburg3,
Nathaniel
Heintz4, and
Jian
Zuo4, 5
1 Department of Neurobiology and Behavior, State
University of New York at Stony Brook, Stony Brook, New York
11794-5230, 2 Department of Neurobiology, Duke University
Medical Center, Durham, North Carolina 27710, 3 Abteilung
Molekulare Neurobiologie, Max-Planck-Institut für medizinische
Forschung, D-69120 Heidelberg, Germany, 4 Laboratory of
Molecular Biology, Howard Hughes Medical Institute, The Rockefeller
University, New York, New York 10021, and 5 Department of
Developmental Neurobiology, St. Jude Children's Research Hospital,
Memphis, Tennessee 38105
Neurodegeneration in Lurcher (Lc) mice results
from constitutive activation of  2, a subunit of ionotropic glutamate
receptors (GluRs) with unknown natural ligands and channel
properties. Homo-oligomeric channels of GluR-2 with the Lurcher
mutation (GluR-2Lc) 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-2Lc 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-2Lc by replacing
glutamine with arginine. Analogous to AMPA/kainate receptors,
GluR-2Lc(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-2Lc
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.
Key words:
glutamate receptors; 2; Lurcher mutation; polyamine
block; Ca2+ permeability; fractional
Ca2+ currents
Copyright © 2000 Society for Neuroscience 0270-6474/00/20165973-08$05.00/0
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