Interdimer Contacts Paint a New Picture of Glutamate Receptor Activation

Abstract

The ionotropic glutamate receptors (iGluR) mediate the majority of the rapid signalling at excitatory synapses in the brain. The binding of glutamate and other agonist molecules to the ligand-binding domains (LBDs) of the iGluR provides the free energy for driving intra-LBD conformational transitions that open the gate of the ion channel. However, much less information is available about inter-LBD motions. We recently showed that disulfide crosslinks between kainate receptor LBD dimers inhibit receptor activation (Das et al, 2010, PNAS). Here, we used a combination of structural studies and electrophysiology to map the conformational transitions of the LBD dimers between different states of the GluA2 receptor. Interdimer disulfide trapping with exquisite functional sensitivity shows that the two subunit dimers must translate relative to each other during activation, with the center of the dimers moving towards the overall axis of the channel. The crosslink captures an intermediate state between resting and fully activated and has geometry (including reduced linker separation) that provides new insight to glutamate receptor activation.