Conformational restriction blocks glutamate receptor desensitization.

Abstract:

:Desensitization is a universal feature of ligand-gated ion channels. Using the crystal structure of the GluR2 L483Y mutant channel as a guide, we attempted to build non-desensitizing kainate-subtype glutamate receptors. Success was achieved for GluR5, GluR6 and GluR7 with intermolecular disulfide cross-links but not by engineering the dimer interface. Crystallographic analysis of the GluR6 Y490C L752C dimer revealed relaxation from the active conformation, which functional studies reveal is not sufficient to trigger desensitization. The equivalent non-desensitizing cross-linked GluR2 mutant retained weak sensitivity to a positive allosteric modulator, which had no effect on GluR2 L483Y. These results establish that the active conformation of AMPA and kainate receptors is conserved and further show that their desensitization requires dimer rearrangements, that subtle structural differences account for their diverse functional properties and that the ligand-binding core dimer is a powerful regulator of ion-channel activity.

journal_name

Nat Struct Mol Biol

authors

Weston MC,Schuck P,Ghosal A,Rosenmund C,Mayer ML

doi

10.1038/nsmb1178

subject

Has Abstract

pub_date

2006-12-01 00:00:00

pages

1120-7

issue

12

eissn

1545-9993

issn

1545-9985

pii

nsmb1178

journal_volume

13

pub_type

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