title: The N-terminal domain modulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization.
abstract: AMPA receptors are tetrameric glutamate-gated ion channels that mediate fast synaptic neurotransmission in mammalian brain. Their subunits contain a two-lobed N-terminal domain (NTD) that comprises over 40% of the mature polypeptide. The NTD is not obligatory for the assembly of tetrameric receptors, and its functional role is still unclear. By analyzing full-length and NTD-deleted GluA1-4 AMPA receptors expressed in HEK 293 cells, we found that the removal of the NTD leads to a significant reduction in receptor transport to the plasma membrane, a higher steady state-to-peak current ratio of glutamate responses, and strongly increased sensitivity to glutamate toxicity in cell culture. Further analyses showed that NTD-deleted receptors display both a slower onset of desensitization and a faster recovery from desensitization of agonist responses. Our results indicate that the NTD promotes the biosynthetic maturation of AMPA receptors and, for membrane-expressed channels, enhances the stability of the desensitized state. Moreover, these findings suggest that interactions of the NTD with extracellular/synaptic ligands may be able to fine-tune AMPA receptor-mediated responses, in analogy with the allosteric regulatory role demonstrated for the NTD of NMDA receptors.
authors.affiliation: From the Division of Biochemistry and Biotechnology, Department of Biosciences, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Tommi
authors.initials: T
authors.lastname: Möykkynen
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Coleman
authors.forename: Artur
authors.initials: A
authors.lastname: Semenov
authors.forename: Kari
authors.initials: K
authors.lastname: Keinänen
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D017434:Protein Structure, Tertiary; D018091:Receptors, AMPA / Q000819:agonists* / Q000378:metabolism*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology*
chemical_list: D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
keywords: Allosteric Regulation; Ion Channels; Ionotropic Glutamate Receptors (AMPA, NMDA); Protein Domains; Receptor Desensitization; Receptor Structure-Function