External ions are coactivators of kainate receptors.
The activation of ligand-gated ion channels is thought to depend solely on the binding of chemical neurotransmitters. In this study, we demonstrate that kainate (KA) ionotropic glutamate receptors (iGluRs) require not only the neurotransmitter L-glutamate (L-Glu) but also external sodium and chloride ions for activation. Removal of external ions traps KA receptors (KARs) in a novel inactive state that binds L-Glu with picomolar affinity. Moreover, occupancy of KARs by L-Glu precludes external ion binding, demonstrating crosstalk between ligand- and ion-binding sites. AMPA iGluRs function normally in the absence of external ions, revealing that even closely related iGluR subfamilies operate by distinct gating mechanisms. This behavior is interchangeable via a single amino acid residue that operates as a molecular switch to confer AMPA receptor behavior onto KARs. Our findings identify a novel allosteric site that singles out KARs from all other ligand-gated ion channels.
Wong
Adrian Y C
AY
Department of Pharmacology and Therapeutics, McGill University, Montreal, Québec, H3A 1Y6, Canada.
Fay
Anne-Marie L
AM
Bowie
Derek
D
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007477:Ions; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding; D018091:Receptors, AMPA / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000187:drug effects* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D007477:Ions; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors