A eukaryotic specific transmembrane segment is required for tetramerization in AMPA receptors

Catherine L. Salussolia, Quan Gan, Rashek Kazi, Puja Singh, Janet Allopenna, Hiro Furukawa, Lonnie P. Wollmuth

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Most fast excitatory synaptic transmission in the nervous system is mediated by glutamate acting through ionotropic glutamate receptors (iGluRs). iGluRs (AMPA, kainate, and NMDA receptor subtypes) are tetrameric assemblies, formed as a dimer of dimers. Still, the mechanism underlying tetramerization-the necessary step for the formation of functional receptors that can be inserted into the plasma membrane-is unknown. All eukaryotic compared to prokaryotic iGluR subunits have an additional transmembrane segment, theM4segment, which positions the physiologically critical C-terminal domain on the cytoplasmic side of the membrane.AMPAreceptor (AMPAR) subunits lacking M4 do not express on the plasma membrane. Here, we show that these constructs are retained in the endoplasmic reticulum, the major cellular compartment mediating protein oligomerization. Using approaches to assay the native oligomeric state of AMPAR subunits, we find that subunits lacking M4 or containing single amino acid substitutions along an "interacting" face of the M4 helix that block surface expression no longer tetramerize in either homomeric or heteromeric assemblies. In contrast, subunit dimerization appears to be largely intact. These experiments define the M4 segment as a unique functional unit in AMPARs that is required for the critical dimer-to-tetramer transition.

Original languageEnglish (US)
Pages (from-to)9840-9845
Number of pages6
JournalJournal of Neuroscience
Volume33
Issue number23
DOIs
StatePublished - 2013

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