Linked Life Data

18690046

Source:http://linkedlifedata.com/resource/pubmed/id/18690046

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2008-8-11
pubmed:abstractText
Differences in binding-site residues of GluR2 (AMPAR) and GluR6 (KAR) subunits have been identified that might account for their functional and pharmacological differences. Specifically, residues A518, A689 and N721 in GluR6 replace highly conserved threonine and serine residues found in other ionotropic glutamate receptor (iGluR) subunits. To define how these natural substitutions impact GluR6 function, we used patch clamp recording with ultrafast perfusion to characterize the effects of A518T, A689S and N721T on agonist potency, efficacy and response kinetics. We find these natural substitutions impact GluR6 function less than would be expected from reverse mutations in other iGluRs. There was little effect of individual or combined mutations on glutamate potency, deactivation or desensitization kinetics. Altered recovery kinetics were seen that were greatest after combined mutations. Kainate potency and response kinetics were also unchanged in the mutants, whereas kainate efficacy was reduced in A518T and increased the T/S/T mutant relative glutamate. Notably, A518T and A689S mutation permitted AMPA to bind as a weak competitive antagonist and the effects of these mutations were additive. N721T mutation further enhanced AMPA binding, allowing AMPA to activate and fully desensitize the receptors. Alternative mutations altering side chain length at position 518 produced far greater changes in glutamate affinity and response kinetics than did the natural mutations. We conclude that these nonconserved residues in GluR6 define the size of the agonist-binding pocket, exerting a steric influence on the bound agonist and the extent of binding-domain closure that can influence agonist potency, deactivation, desensitization and recovery kinetics.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1933-6969
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
1
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
417-28
pubmed:dateRevised
2010-1-15
pubmed:meshHeading
pubmed:articleTitle
Functional consequences of natural substitutions in the GluR6 kainate receptor subunit ligand-binding site.
pubmed:affiliation
Albany Medical College, Center for Neuroscience and Neuropharmacology, Albany, New York, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural