M.K.S. and V.P. contributed equally to this work.
Dominance of the lurcher mutation in heteromeric kainate and AMPA receptor channels
Article first published online: 20 DEC 2001
European Journal of Neuroscience
Volume 14, Issue 5, pages 861–868, September 2001
How to Cite
Schwarz, M. K., Pawlak, V., Osten, P., Mack, V., Seeburg, P. H. and Köhr, G. (2001), Dominance of the lurcher mutation in heteromeric kainate and AMPA receptor channels. European Journal of Neuroscience, 14: 861–868. doi: 10.1046/j.0953-816x.2001.01705.x
- Issue published online: 20 DEC 2001
- Article first published online: 20 DEC 2001
- Received 21 February 2001, revised 25 June 2001, accepted 6 July 2001
- constitutive activation;
- HEK293 cells;
- pore size;
- surface expression;
- unliganded gating
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 (KA2Lc), are retained inside the cell but are surface-expressed when assembled with GluR6 sununits. Importantly, KA2Lc dominates the gating of KA2Lc/GluR6WT 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-BLc(Q) which forms spontaneously active homomeric channels with rectifying current-voltage relationships, dominates the gating of heteromeric GluR-BLc(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 GluRLc and heteromeric GluRLc/GluRWT channels.