AMPA receptor function is altered in GLUR2-deficient mice.
The GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor determines many of the biophysical properties of native AMPA receptors, including Ca++ permeability. Genetically engineered mice unable to edit the Q to R site of the GluR2 subunit die within 3 wk postpartum, presumably due to toxicity associated with enhanced Ca++ influx through AMPA receptors. In contrast, disruption of the gene encoding GluR2 is not necessarily lethal. The objective of this study was to explore potential mechanisms that permit survival of GluR2 (-/-) mice despite AMPA receptors that are highly Ca++ permeable. Whole-cell, patch-clamp recording of AMPAreceptor responses in cortical pyramidal cells revealed that the kinetics of recovery from desensitization were significantly slower for receptors from GluR2 (-/-) mice compared to receptors from GluR2 (+/+) mice. The recovery time constants for AMPA receptors from GluR2 (-/-) and GluR2 (+/+) mice were 109.8 +/- 17 ms and 54.4 +/- 7.1 ms, respectively. The slower recovery kinetics would be expected to reduce Ca++ influx during repetitive stimulation. Because both RNA editing at the R/G site and alternative splicing of the flip and flop module affect AMPA receptor desensitization recovery rates, the possibility that these mechanisms were changed in GluR2 (-/-) mice was investigated. On a macroscopic level, neither editing nor splicing of the GluR-1, 3 or 4 subunits were changed in GluR2 (-/-) mice compared to GluR2 (+/+) mice. In summary, an increase in the time constant for recovery from desensitization may contribute to the ability of GluR2 (-/-) to survive.
Harvey
S C
SC
Neuroscience Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285-0510, USA.
Köster
A
A
Yu
H
H
Skolnick
P
P
Baumbarger
P
P
Nisenbaum
E S
ES
D000818:Animals; D001921:Brain / Q000166:cytology / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D005260:Female; D018390:Gene Targeting; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D021122:Protein Subunits; D017393:RNA Editing; D012326:RNA Splicing; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*
D021122:Protein Subunits; D018091:Receptors, AMPA; D018698:Glutamic Acid; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium