Gan, Quan; Dai, Jian; Zhou, Huan-Xiang; Wollmuth, Lonnie P.
The Transmembrane Domain Mediates Tetramerization of -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors
JOURNAL OF BIOLOGICAL CHEMISTRY, 291:6595-6606, MAR 18 2016

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.

DOI:10.1074/jbc.M115.686246

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