Effects of the lurcher mutation on GluR1 desensitization and activation kinetics

Rebecca Meier Klein; James R Howe

doi:10.1523/JNEUROSCI.0660-04.2004

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Effects of the lurcher mutation on GluR1 desensitization and activation kinetics

Journal article

Open access

Peer reviewed

Effects of the lurcher mutation on GluR1 desensitization and activation kinetics

Rebecca Meier Klein and James R Howe

The Journal of neuroscience, Vol.24(21), pp.4941-4951

05/26/2004

DOI: 10.1523/JNEUROSCI.0660-04.2004

PMCID: PMC6729373

PMID: 15163686

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Abstract

Previous studies of the lurcher mutation in GluR1 channels concluded that its main effect is to create constitutively active channels (Kohda et al., 2000; Taverna et al., 2000). GluR1Lc channels also exhibit slowed kinetics and a shift in their apparent affinity for glutamate (Kohda et al., 2000; Taverna et al., 2000). Here, we have undertaken a kinetic analysis of GluR1Lc channels to quantify the effects of lurcher and to determine the relative contribution of these effects to the lurcher phenotype. Analysis of GluR1Lc leak current demonstrated that the 2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulfonamide (NBQX)-sensitive portion of the leak current corresponded to a current generated by glutamate concentrations similar to the levels of contaminating glutamate measured in our normal external solutions. This result, and the small size of the leak current relative to the currents evoked by saturating glutamate, indicates that GluR1Lc channels exhibit little or no constitutive activity. Our results indicate that the primary effect of the lurcher mutation is to increase the affinity of GluR1 for glutamate and reduce the desensitization of GluR1 at nanomolar concentrations. We also found that the mutation makes both the rate and extent of GluR1Lc channel desensitization depend strongly on subunit occupancy. We conclude that the poor survival of GluR1Lc-transfected cells, and presumably cerebellar neurons in lurcher mice, results because channels carrying the lurcher mutation open and do not desensitize at ambient levels of glutamate.

Mice, Neurologic Mutants - genetics

Cerebellum - metabolism

Cells, Cultured

Excitatory Amino Acid Antagonists - pharmacology

Dose-Response Relationship, Drug

Quinoxalines - pharmacology

Patch-Clamp Techniques

Animals

Models, Biological

Glutamic Acid - metabolism

Mice

Mutation

Monte Carlo Method

Receptors, AMPA - genetics

Receptors, AMPA - metabolism

Receptors, AMPA - antagonists & inhibitors

Details

Title: Subtitle: Effects of the lurcher mutation on GluR1 desensitization and activation kinetics
Creators: Rebecca Meier Klein - Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA
James R Howe
Resource Type: Journal article
Publication Details: The Journal of neuroscience, Vol.24(21), pp.4941-4951
Publisher: United States
DOI: 10.1523/JNEUROSCI.0660-04.2004
PMID: 15163686
PMCID: PMC6729373
ISSN: 0270-6474
eISSN: 1529-2401
Grant note: GM58926 / NIGMS NIH HHS
Language: English
Date published: 05/26/2004
Academic Unit: Surgery
Record Identifier: 9984051571402771

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