Subunit interactions and AMPA receptor desensitization.
Most AMPA-type glutamate receptors (GluRs) exhibit rapid and virtually complete desensitization when activated by glutamate, and at some central synapses it is largely desensitization that determines the decay of EPSCs. However, the mechanisms underlying the conformation change that results in desensitization are not fully understood. AMPA receptor subunits that contain a single amino acid substitution have been shown to form homomeric channels that show markedly reduced desensitization. We show here that the coexpression of wild-type GluR1 with one such mutant, GluR1(L497Y), results in heteromeric channels that show desensitization behavior that is intermediate between wild-type and mutant homomers. The relative amplitudes of the multiple exponential components present in the decay of glutamate-evoked currents depended on the relative abundance of wild-type and mutant subunits and were described by the combinatorial distribution of the two types of subunits into tetrameric, but not pentameric, assemblies. Our results are consistent with recent structural data suggesting that AMPA receptors are tetrameric assemblies composed of two dimers.
Robert
A
A
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
Irizarry
S N
SN
Hughes
T E
TE
Howe
J R
JR
D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D019281:Dimerization; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008959:Models, Neurological; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011485:Protein Binding; D021122:Protein Subunits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D018698:Glutamic Acid; D021122:Protein Subunits; D018091:Receptors, AMPA