title: Role of dimer interface in activation and desensitization in AMPA receptors.
abstract: The conversion of chemical to electrical signals by the AMPA receptors is the key step by which these proteins control cognitive and motor responses. Here, we have used luminescence resonance energy transfer (LRET) to gain insight into the conformational changes induced by glutamate binding in the agonist-binding domain in functional AMPA receptors expressed in oocytes and HEK-293 cells. The LRET-based distances indicate that the interface between the upper lobes of the agonist-binding domain within a dimer is in a decoupled state in the unligated Apo state of the receptor. Agonist binding results in the formation of the dimer interface in the open-channel form of the receptor. In the continued presence of glutamate when the receptor is primarily in the desensitized state, the dimer interface is decoupled, confirming that the decoupling of the dimer interface leads to channel closure. The LRET distances also indicate that the dimer interface is preformed before activation in the L484Y mutation and also is formed in the antagonist (ZK200775)-bound form of the AMPA receptor. These results suggests that, although the preformation of the interface is not sufficient to drive channel activation, it could play a role in the energetics of activation and hence modulation of the receptor by auxiliary proteins or small molecules.
authors.affiliation: Center for Membrane Biology, Department of Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, TX 77030, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gonzalez
authors.forename: Mei
authors.initials: M
authors.lastname: Du
authors.forename: Kodeeswaran
authors.initials: K
authors.lastname: Parameshwaran
authors.forename: Vishnu
authors.initials: V
authors.lastname: Suppiramaniam
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Jayaraman
mesh_terms: D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D018091:Receptors, AMPA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D018091:Receptors, AMPA
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