Physical interaction of Jab1 with human serotonin 6 G-protein-coupled receptor and their possible roles in cell survival

Hyung Mun Yun, Ja Hyun Baik, Insug Kang, Changbae Jin, Hyewhon Rhim

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Abstract

The 5-HT6 receptor (5-HT6R) is one of the most recently cloned serotonin receptors, and it plays important roles in Alzheimer disease, depression, and learning and memory disorders. However, unlike the other serotonin receptors, the cellular mechanisms of 5-HT6R are poorly elucidated relative to its significance in human brain diseases. Here, using a yeast two-hybrid assay, we found that the human 5-HT6R interacts with Jun activation domain-binding protein-1 (Jab1). We also confirmed a physical interaction between 5-HT6R and Jab1 using glutathione S-transferase pulldown, fluorescence resonance energy transfer, co-immunoprecipitation, and immunocyto(histo)-chemistry assays. The manipulation of Jab1 expression using Jab1 small interference RNA decreased 5-HT 6R-mediated activity and cell membrane expression of 5-HT 6R, whereas overexpression of Jab1 produced no significant effect. In addition, we demonstrated that the activation of 5-HT6R induced the translocation of Jab1 into the nucleus and increased c-Jun phosphorylation and the interaction between Jab1 and c-Jun. Furthermore, we found that 5-HT 6R and Jab1 were up-regulated in middle cerebral artery occlusion-induced focal cerebral ischemic rats and in cultured cells exposed to hypoxic insults, suggesting possible protective roles for 5-HT6R and Jab1. These findings suggest that Jab1 provides a novel signal transduction pathway for 5-HT6R and may play an important role in 5-HT 6R-mediated behavior changes in the brain.

Original languageEnglish
Pages (from-to)10016-10029
Number of pages14
JournalJournal of Biological Chemistry
Volume285
Issue number13
DOIs
Publication statusPublished - 2010 Mar 26

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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