Crosslinking the ligand‐binding domain dimer interface locks kainate receptors out of the main open state. (2nd July 2013)

• Record Type: Journal Article
• Authors: Daniels, Bryan A.; Andrews, Elizabeth D.; Aurousseau, Mark R. P.; Accardi, Michael V.; Bowie, Derek
• Is Part Of: Journal of physiology. Volume 591:Number 16(2013:Aug.)
• Page Start: 3873
• Page End: 3885
• Publication Date: 2013-07-02
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2013.253666
• Languages: English
• ISSNs: 0022-3751

Abstract

Key points: This study identifies the gating structure responsible for controlling ion‐channel subconductance behaviour at a major neurotransmitter receptor, namely kainate‐type ionotropic glutamate receptor. Evidence is provided that the activation process may be made up of two clearly distinct conductance phases. The study speculates that functional diversity amongst ionotropic glutamate receptors emerged during evolution by re‐deploying the same structures to carry out different tasks. Abstract Kainate‐selective ionotropic glutamate receptors (iGluRs) fulfil key roles in the CNS, making them the subject of detailed structural and functional analyses. Although they are known to gate a channel pore with high and low ion‐permeation rates, it is still not clear how switches between these gating modes are achieved at the structural level. Here, we uncover an unexpected role for the ligand‐binding domain (LBD) dimer assembly in this process. Covalent crosslinking of the dimer interface keeps kainate receptors out of the main open state but permits access to lower conductance states suggesting that significant rearrangements of the dimer interface are required for the receptor to achieve full activation. These observations differ from NMDA‐selective iGluRs where constraining dimer movement reduces open‐channel probability. In contrast, our data show that restricting movement of the dimer interface interferes with conformational changes that underlie both activation and desensitization. Working within the limits of a common architectural design, we propose functionally diverse iGluR families were able to emerge during evolution by re‐deploying existing gating structures to fulfil different tasks.