title: The Transmembrane Domain Mediates Tetramerization of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors.
abstract: AMPA receptors (AMPARs) mediate fast excitatory neurotransmission in the central nervous system. Functional AMPARs are tetrameric complexes with a highly modular structure, consisting of four evolutionarily distinct structural domains: an amino-terminal domain (ATD), a ligand-binding domain (LBD), a channel-forming transmembrane domain (TMD), and a carboxyl-terminal domain (CTD). Here we show that the isolated TMD of the GluA1 AMPAR is fully capable of tetramerization. Additionally, removal of the extracellular domains from the receptor did not affect membrane topology or surface delivery. Furthermore, whereas the ATD and CTD contribute positively to tetramerization, the LBD presents a barrier to the process by reducing the stability of the receptor complex. These experiments pinpoint the TMD as the "tetramerization domain" for AMPARs, with other domains playing modulatory roles. They also raise intriguing questions about the evolution of iGluRs as well as the mechanisms regulating the biogenesis of AMPAR complexes.
authors.affiliation: Graduate Program in Neuroscience, From the Department of Neurobiology and Behavior.
authors.forename: Quan
authors.initials: Q
authors.lastname: Gan
authors.affiliation: the Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida 32306.
authors.forename: Jian
authors.initials: J
authors.lastname: Dai
authors.affiliation: the Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida 32306.
authors.forename: Huan-Xiang
authors.initials: HX
authors.lastname: Zhou
authors.affiliation: From the Department of Neurobiology and Behavior, the Department of Biochemistry and Cell Biology, and the Center for Nervous System Disorders, Stony Brook University, Stony Brook, New York 11794-5230 and lonnie.wollmuth@stonybrook.edu.
authors.forename: Lonnie P
authors.initials: LP
authors.lastname: Wollmuth
mesh_terms: D000818:Animals; D001665:Binding Sites; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D021381:Protein Transport; D051381:Rats; D018091:Receptors, AMPA / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018091:Receptors, AMPA
keywords: amino-terminal domain; endoplasmic reticulum (ER); ion channel; ionotropic glutamate receptor; ligand-binding domain; native PAGE; protein assembly; synapse
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