Dominance of the lurcher mutation in heteromeric kainate and AMPA receptor channels

Schwarz, M. K., Pawlak, V., Osten, P., Mack, V., Seeburg, P. H., Köhr, G. (2002) Dominance of the lurcher mutation in heteromeric kainate and AMPA receptor channels. European Journal of Neuroscience, 14 (5). pp. 861-868. ISSN 0953816X (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/11576190
DOI: 10.1046/j.0953-816X.2001.01705.x

Abstract

Homomeric glutamate receptor (GluR) channels become spontaneously active when the last alanine residue within the invariant SYTANLAAF-motif in the third membrane segment is substituted by threonine. The same mutation in the orphan GluRδ2 channel is responsible for neurodegeneration in 'Lurcher' (Lc) mice. Since most native GluRs are composed of different subunits, we investigated the effect of an Lc-mutated subunit in heteromeric kainate and AMPA receptors expressed in HEK293 cells. Kainate receptor KA2 subunits, either wild type or carrying the Lc mutation (KA2 Lc), are retained inside the cell but are surface-expressed when assembled with GluR6 sununits. Importantly, KA2 Lc dominates the gating of KA2 Lc/GluR6 WT channels, as revealed by spontaneous activation and by slowed desensitization and deactivation kinetics of ligand-activated whole-cell currents. Moreover, the AMPA receptor subunit GluR-B Lc(Q) which forms spontaneously active homomeric channels with rectifying current-voltage relationships, dominates the gating of heteromeric GluR-B Lc(Q)/GluR-A(R) channels. The spontaneous currents of these heteromeric AMPAR channels show linear current-voltage relationships, and the ligand-activated whole-cell currents display slower deactivation and desensitization kinetics than the respective wild-type channels. For heteromeric Lc-mutated kainate and AMPA receptors, the effects on kinetics were reduced relative to the homomeric Lc-mutated forms. Thus, an Lc-mutated subunit can potentially influence heteromeric channel function in vivo, and the severity of the phenotype will critically depend on the levels of homomeric GluR Lc and heteromeric GluR Lc/GluR WT channels.

Item Type: Paper
Uncontrolled Keywords: Constitutive activation HEK293 cells Pore size Surface expression Unliganded gating AMPA receptor glutamate receptor kainic acid receptor receptor subunit article controlled study desensitization electric potential electrophysiology human human cell in vivo study kinetics mutation phenotype porosity priority journal protein expression
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > AMPA receptor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > glutamate receptor
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Osten lab
Depositing User: Matt Covey
Date: 2002
Date Deposited: 05 Apr 2013 01:52
Last Modified: 05 Apr 2013 01:52
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28099

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