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Molecular and Genomic Physiology |
1 Department of Pharmacology and Therapeutics, McGill University, Montreal, Québec, Canada
The agonist-binding domain of ionotropic glutamate receptors (iGluRs) has recently been crystallized as two polypeptide chains with a linker region. Although work on the structure of this isolated ligand-binding core has been invaluable, there is debate over how it relates to conformations adopted by intact receptors. iGluR crystals are proposed to represent the activated state as their degree of domain closure correlates well with agonist efficacy. However, iGluR crystals exhibit high agonist affinity that more closely matches that of desensitized receptors. Consequently, conformations adopted by iGluR crystals may represent this state. To test this, we have employed the plant lectin, concanavalin-A (Con-A) to report conformational changes elicited by kainate (KA) iGluR agonists during desensitization. When GluR6 KA receptors (KARs) were pre-incubated with Con-A, equilibrium responses evoked by the full agonist, L-glutamate (L-Glu), increased almost 30-fold. However, in the continued presence of L-Glu, Con-A exerted no effect suggesting that it has restricted access to its binding sites when the agonist is bound. However, Con-A does not discriminate well between agonist-bound or -unbound states with the weak partial agonist, domoate. Accessibility experiments with KA were intermediate in nature consistent with its equilibrium efficacy at GluR6 KARs. Our results suggest that full and partial agonists elicit distinct conformational changes in KARs during desensitization. This finding can be reconciled with crystallographic data if the agonist-binding domain adopts the same conformation in the activated and desensitized states. However, other interpretations are possible suggesting future work is required if this issue is to be resolved.
(Received 13 December 2005;
accepted after revision 23 January 2006;
first published online 26 January 2006)
Corresponding author D. Bowie: Department of Pharmacology and Therapeutics, McIntyre Medical Sciences Building, Room 1317, McGill University, 3655 Promenade Sir William Osler, Montreal, Québec, Canada H3A 1Y6. Email: derek.bowie{at}mcgill.ca
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