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Disulfide bonding and cysteine accessibility in the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit GluRD

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Abele,  Rupert
Max Planck Research Group Ion Channel Structure (Dean R. Madden), Max Planck Institute for Medical Research, Max Planck Society;

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Madden,  Dean R.
Max Planck Research Group Ion Channel Structure (Dean R. Madden), Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Abele, R., Lampinen, M., Keinänen, K., & Madden, D. R. (1998). Disulfide bonding and cysteine accessibility in the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit GluRD. The Journal of Biological Chemistry, 273(39), 25132-25138. doi:10.1074/jbc.273.39.25132.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-9B6F-8
Abstract
Redox agents elicit a wide variety of effects on the ligand affinity and channel properties of ionotropic glutamate receptors and have been proposed as potential therapeutic agents for neuropathological processes. One such effect is the dithiothreitol (DTT)-induced increase in agonist affinity of certain ionotropic glutamate receptors (GluRs), presumably due to reduction of a disulfide bridge formed between cysteine residues conserved among all GluRs. Using biochemical techniques, this disulfide is shown to exist in the ligand-binding domain of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluRD, although GluRD homomeric receptors are not modulated by DTT. The disulfide is inaccessible to DTT, explaining the insensitivity of the intact receptor. Single mutants C260S and C315S show a 2–3-fold higher ligand affinity than wild-type, as observed for several intact GluRs, indicating that the affinity switch is completely contained within the ligand-binding domain. Also, mutants lacking the native disulfide show non-native oligomerization and dramatically reduced specific activity. These facts suggest that the disulfide bridge is required for the stability of the ligand-binding domain, explaining its conservation. A third cysteine residue in the ligand-binding domain exists as a free thiol, partially sequestered in a hydrophobic environment. These results provide a framework for interpreting a variety of GluR redox modulatory phenomena.