Multiple trafficking signals regulate kainate receptor KA2 subunit surface expression

Zhao Ren, Nathan J. Riley, Elizabeth P. Garcia, James M. Sanders, Geoffrey T. Swanson, John Marshall*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

The kainate receptor subunit KA2 does not form functional homomeric channels despite its structural similarity to the functional glutamate receptor 5-7 subunits and high agonist binding affinity in in vitro assays. In this study, we first demonstrate that homomeric KA2 receptors fail to reach the plasma membrane and then identify the molecular mechanisms preventing surface expression. Specifically, we show that KA2 subunits form homooligomeric receptors that are confined to the endoplasmic reticulum (ER). We then demonstrate that, in both heterologous expression systems and primary neurons, the intracellular retention of KA2 is not caused by subunit misfolding but, rather, is mediated through discrete protein trafficking signals, including an arginine-rich ER retention/retrieval motif and a di-leucine endocytic sequence in the C terminus of the KA2 subunit. Disruption of these motifs results in ER exit and surface expression of KA2 homomeric receptors that remain nonfunctional. Furthermore, our data suggest that the ER retention/retrieval signal in KA2 is sterically shielded during heteromeric assembly, allowing delivery of functional heteromeric receptors to the plasma membrane. Taken together, our results illustrate novel regulatory mechanisms that control the intracellular trafficking and surface expression of kainate receptors.

Original languageEnglish (US)
Pages (from-to)6608-6616
Number of pages9
JournalJournal of Neuroscience
Volume23
Issue number16
DOIs
StatePublished - Jul 23 2003

Keywords

  • Arginine-rich motif
  • Di-leucine motif
  • ER retention
  • Heteromeric assembly
  • Intracellular trafficking
  • KA2 subunit
  • Kainate receptors

ASJC Scopus subject areas

  • Neuroscience(all)

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