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Functional characterization and in silico docking of full and partial GluK2 kainate receptor agonists.

Abstract：

:Two structural models have been developed to explain how agonist binding leads to ionotropic glutamate receptor (iGluR) activation. At alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) iGluRs, full and partial agonists close the agonist-binding domain (ABD) to different degrees whereas agonist-induced domain closure is apparently fixed at N-methyl-D-aspartate receptors. Although kainate (KA) iGluRs are thought to behave like AMPA receptors, the issue has not been formally tested because of the paucity of available receptor agonists. Here we identify a series of structurally related full and partial agonists at GluK2 (formerly GluR6) KARs and predict their docking mode using the in silico ligand-docking program FITTED. As expected, the neurotransmitter L-Glu behaved as a full agonist but modest reduction (e.g., L-serine or L-aspartate) or elongation (e.g., L-alpha-aminoadipate) in chain length generated weak partial agonists. It is noteworthy that in silico ligand-docking predicted that most partial agonists select for the closed and not, as expected, the open or intermediate conformations of the GluK2 ABD. Experiments using concanavalin-A to directly report conformations in the intact GluK2 receptor support this prediction with the full agonist, L-Glu, indistinguishable in this regard from weak partial agonists, D- and L-Asp. Exceptions to this were KA and domoate, which failed to elicit full closure as a result of steric hindrance by a key tyrosine residue. Our data suggest that alternative structural models need to be considered to describe agonist behavior at KARs. Finally, our study identifies the responsiveness to several neurotransmitter candidates establishing the possibility that endogenous amino acids other than L-Glu may regulate native KARs at central synapses.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Fay AM,Corbeil CR,Brown P,Moitessier N,Bowie D

doi

10.1124/mol.108.054254

subject

Has Abstract

pub_date

2009-05-01 00:00:00

pages

1096-107

issue

5

eissn

0026-895X

issn

1521-0111

pii

mol.108.054254

journal_volume

75

pub_type

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