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

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. [ABSTRACT FROM AUTHOR]