| Abstract No.: | C-B3054 |
| Country: | Canada |
| | |
| Title: | IDENTIFICATION OF A NOVEL TYPE OF ENDOGENOUS ANTAGONIST AT IONOTROPIC KAINATE GLUTAMATE RECEPTORS |
| | |
| Authors/Affiliations: | 1 Anne-Marie Fay*; 1 Christopher Corbeil; 1 Nicolas Moitessier; 1 Derek Bowie;
1 McGill University, Montreal, QC, Canada
|
| | |
| Content: | Objective: Ligand-gated ion-channels (LGICs) are exquisitely designed to respond to specific small neurotransmitters at synapses. Although the architectural arrangement of their ligand-binding domain varies across different ion-channel families, it has been generally assumed that the ligand-binding domain of all LGICs bind two distinct classes of molecule. Agonists bind to the ligand-binding domain, which, in turn harness the binding energy to drive conformational changes that cause ion-channel opening. In contrast, competitive antagonists bind to the ligand-binding domain, but do not promote conformational changes in the pore. Here, we identify a novel type of antagonist which binds to the ligand-binding domain of iGluRs. This ligand elicits conformational changes like full agonists but fails to gate the ion-channel pore.
Materials & Methods: To identify novel KAR ligands, we have tested the ability of a series of L-Glu analogs to activate or inhibit kainate receptors using electrophysiology. To determine if agonist efficacy correlates with closure of the ligand-binding domain, we have used a molecular docking program to determine the conformation adopted by the ligand-binding of GluR6 kainate receptors for each ligand.
Results & Conclusion: Here we show that the degree of conformational change in the ligand-binding domain does not correlate with agonist efficacy contrary to current models of AMPA and kainate receptor gating. This conclusion is supported by experiments with the plant lectin, Concanavalin-A, which was used as a reporter of conformational changes in the ligand-binding domain. Moreover, we demonstrate that unlike the channel blocker, philanthotoxin, or the competitive antagonist, CNQX, this novel type of antagonist induces conformational changes comparable to full agonists at kainate receptors. Interestingly, this property is shared by both the D- and L- isomers of the endogenous amino acids, aspartate and serine. Given that both stereoisomers are found in the developing CNS, our work points to a novel mechanism that may regulate kainate receptors.
Support contributed by: FRSQ doctoral award, CIHR, CRC, CFI, RQCHP.
|
| | |
| Back |
|
