Structural basis for partial agonist action at ionotropic glutamate receptors

Rongsheng Jin, Tue G. Banke, Mark L. Mayer, Stephen F. Traynelis, Eric Gouaux

Research output: Contribution to journalArticle

313 Citations (Scopus)

Abstract

An unresolved problem in understanding neurotransmitter receptor function concerns the mechanism(s) by which full and partial agonists elicit different amplitude responses at equal receptor occupancy. The widely held view of 'partial agonism' posits that resting and active states of the receptor are in equilibrium, and partial agonists simply do not shift the equilibrium toward the active state as efficaciously as full agonists. Here we report findings from crystallographic and electrophysiological studies of the mechanism of activation of an AMPA-subtype glutamate receptor ion channel. In these experiments, we used 5-substituted willardiines, a series of partial agonists that differ by only a single atom. Our results show that the GluR2 ligand-binding core can adopt a range of ligand-dependent conformational states, which in turn control the open probability of discrete subconductance states of the intact ion channel. Our findings thus provide a structure-based model of partial agonism.

Original languageEnglish (US)
Pages (from-to)803-810
Number of pages8
JournalNature Neuroscience
Volume6
Issue number8
DOIs
StatePublished - Aug 1 2003
Externally publishedYes

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Ionotropic Glutamate Receptors
Ion Channels
Ligands
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Neurotransmitter Receptor
Glutamate Receptors

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Structural basis for partial agonist action at ionotropic glutamate receptors. / Jin, Rongsheng; Banke, Tue G.; Mayer, Mark L.; Traynelis, Stephen F.; Gouaux, Eric.

In: Nature Neuroscience, Vol. 6, No. 8, 01.08.2003, p. 803-810.

Research output: Contribution to journalArticle

Jin, Rongsheng ; Banke, Tue G. ; Mayer, Mark L. ; Traynelis, Stephen F. ; Gouaux, Eric. / Structural basis for partial agonist action at ionotropic glutamate receptors. In: Nature Neuroscience. 2003 ; Vol. 6, No. 8. pp. 803-810.
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