Block of kainate receptor desensitization uncovers a key trafficking checkpoint.
A prominent feature of ionotropic glutamate receptors from the AMPA and kainate subtypes is their profound desensitization in response to glutamate-a process thought to protect the neuron from overexcitation. In AMPA receptors, it is well established that desensitization results from rearrangements of the interface formed between agonist-binding domains of adjacent subunits; however, it is unclear how this mechanism applies to kainate receptors. Here we show that stabilization of the binding domain dimer by the generation of intermolecular disulfide bonds apparently blocked desensitization of the kainate receptor GluR6. This result establishes a common desensitization mechanism in both AMPA and kainate receptors. Surprisingly, however, surface expression of these nondesensitizing mutants was drastically reduced and did not depend on channel activity. Therefore, in addition to its role at the synapse, we now propose an intracellular role for desensitization in controlling maturation and trafficking of glutamate receptors.
Priel
Avi
A
The Institute of Basic Dental Sciences, The Hebrew University-Hadassah Dental School, 91120 Jerusalem, Israel.
Selak
Sanja
S
Lerma
Juan
J
Stern-Bach
Yael
Y
D000818:Animals; D002478:Cells, Cultured; D003545:Cysteine / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000502:physiology; D018092:Kainic Acid Receptors / Q000737:chemistry / Q000502:physiology*; D013329:Structure-Activity Relationship; D014162:Transfection / Q000379:methods; D014981:Xenopus; D000097806:GluK2 Kainate Receptor
D003545:Cysteine; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D049452:Green Fluorescent Proteins; D007608:Kainic Acid; D011810:Quinoxalines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline