The BTB/kelch protein, KRIP6, modulates the interaction of PICK1 with GluR6 kainate receptors

Fernanda Laezza, Timothy J. Wilding, Sunitha Sequeira, Ann Marie Craig, James E. Huettner

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Neuronal proteins of the BTB/kelch and PDZ domain families interact with different regions of the cytoplasmic C-terminal domain of the GluR6 kainate receptor subunit. The BTB/kelch protein KRIP6 binds within a 58 amino acid segment of GluR6 proximal to the plasma membrane. In contrast, PDZ domain proteins, such as PICK1 and PSD95, interact with the last 4 residues of the GluR6 C-terminus. KRIP6 reduces peak currents mediated by recombinant GluR6 receptors and by native kainate receptors in neurons, whereas PICK1 stabilizes kainate receptors at synapses. Thus, protein-protein interactions at the C-terminal domain of GluR6 are important for regulating kainate receptor physiology. Here, we show by co-clustering and co-immunoprecipitation that KRIP6 interacts with PICK1 in heterologous cells. In addition, we demonstrate a novel modulation of GluR6 receptors by PICK1 resulting in increased peak current and relative desensitization of GluR6-mediated currents, phenotypes opposite to those produced by KRIP6. Importantly, these effects cancel out when KRIP6 and PICK1 are co-expressed together with GluR6. KRIP6 and PICK1 strongly co-cluster and co-immunoprecipitate regardless of the presence of GluR6. Immunofluorescence analysis reveals that GluR6 can either join the KRIP6-PICK1 clusters or remain separate; however, co-expression of KRIP6 reduces the fraction of PICK1 that co-immunoprecipitates with GluR6. Taken together, these results indicate that, in addition to a previously demonstrated direct interaction with the GluR6 C-terminal domain, KRIP6 regulates kainate receptors by inhibiting PICK1 modulation via competition or a mutual blocking effect.

Original languageEnglish (US)
Pages (from-to)1131-1139
Number of pages9
JournalNeuropharmacology
Volume55
Issue number7
DOIs
StatePublished - Dec 1 2008
Externally publishedYes

Keywords

  • Desensitization
  • Hippocampus
  • Immunofluorescence
  • PDZ domain
  • Patch-clamp

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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