Journal article
Unitary Properties of AMPA Receptors with Reduced Desensitization
Biophysical journal, Vol.113(10), pp.2218-2235
11/21/2017
DOI: 10.1016/j.bpj.2017.07.030
PMCID: PMC5700247
PMID: 28863863
Abstract
Wild-type AMPA receptors display a characteristic rapidly desensitizing phenotype. Many studies point to the dimer interface between pairs of extracellular ligand binding domains as the key region controlling the rate at which the receptors desensitize. However, mutations at the extracellular end of the pore-forming regions (near the putative ion channel gate) have also been shown to alter desensitization. Here we report the behavior of single GluA4 receptors carrying one of two mutations that greatly reduce desensitization at the level of ensemble currents: the dimer interface mutation L484Y and the Lurcher mutation (A623T, GluA4-Lc) in the extracellular end of M3 (the second true transmembrane helix). Analysis of unitary currents in patches with just one active receptor showed that each mutation greatly prolongs bursts of openings without prolonging the apparent duration of individual openings. Each mutation decreases the frequency with which individual receptors visit desensitized states, but both mutant receptors still desensitize multiple times per second. Cyclothiazide (CTZ) reduced desensitization of wild-type receptors and both types of mutant receptor. Analysis of shut-time distributions revealed a form of short-lived desensitization that was resistant to CTZ and was especially prominent for GluA4-Lc receptors. Despite reducing desensitization of GluA4 L484Y receptors, CTZ decreased the amplitude of ensemble currents through GluA2 and GluA4 LY receptor mutants. Single-channel analysis and comparison of the GluA2 L483Y ligand binding domain dimer in complex with glutamate with and without CTZ is consistent with the conclusion that CTZ binding to the dimer interface prevents effects of the LY mutation to modulate receptor activation, resulting in a reduction in the prevalence of large-conductance substates that accounts for the decrease in ensemble current amplitudes. Together, the results show that similar nondesensitizing AMPA-receptor phenotypes of population currents can arise from distinct underlying molecular mechanisms that produce different types of unitary activity.
Details
- Title: Subtitle
- Unitary Properties of AMPA Receptors with Reduced Desensitization
- Creators
- Wei Zhang - Yale UniversityClarissa Eibl - Humboldt-Universität zu BerlinAutumn M. Weeks - Yale UniversityIrene Riva - Humboldt-Universität zu BerlinYan-jun Li - Hebei Medical UniversityAndrew J. R. Plested - Humboldt-Universität zu BerlinJames R. Howe - Yale University
- Resource Type
- Journal article
- Publication Details
- Biophysical journal, Vol.113(10), pp.2218-2235
- Publisher
- Elsevier
- DOI
- 10.1016/j.bpj.2017.07.030
- PMID
- 28863863
- PMCID
- PMC5700247
- ISSN
- 0006-3495
- eISSN
- 1542-0086
- Number of pages
- 18
- Grant note
- Yale University grant J3682-B21 / Erwin-Schrodinger Postdoctoral Fellowship of the Austrian Science Fund (FWF); Austrian Science Fund (FWF) 81573416; 31200808 / National Science Foundation of China (NSFC); National Natural Science Foundation of China (NSFC) EXC-257 / DFG Cluster of Excellence "NeuroCure''; German Research Foundation (DFG) R01NS057725; R56NS057725 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) FOR 2518 / Deutsche Forschungsgemeinschaft (DFG) "DynIon''; German Research Foundation (DFG) DFG PL619-3 / DFG; German Research Foundation (DFG) Chinese Ministry of Education Young Thousand Talent Program NS057725 / National Institutes of Health (NIH) grant; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 11/21/2017
- Academic Unit
- Surgery
- Record Identifier
- 9984322781702771
Metrics
21 Record Views