Regulation of the voltage-gated K+ channels KCNQ2/3 and KCNQ3/5 by ubiquitination: Novel role for Nedd4-2

Jenny Ekberg, Friderike Schuetz, Natasha A. Boase, Sarah Jane Conroy, Jantina Manning, Sharad Kumar, Philip Poronnik*, David J. Adams

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

70 Citations (Scopus)

Abstract

The muscarine-sensitive K+ current (M-current) stabilizes the resting membrane potential in neurons, thus limiting neuronal excitability. The M-current is mediated by heteromeric channels consisting of KCNQ3 subunits in association with either KCNQ2 or KCNQ5 subunits. The role of KCNQ2/3/5 in the regulation of neuronal excitability is well established; however, little is known about the mechanisms that regulate the cell surface expression of these channels. Ubiquitination by the Nedd4/Nedd4-2 ubiquitin ligases is known to regulate a number of membrane ion channels and transporters. In this study, we investigated whether Nedd4/Nedd4-2 could regulate KCNQ2/3/5 channels. We found that the amplitude of the K+ currents mediated by KCNQ2/3 and KCNQ3/5 were reduced by Nedd4-2 (but not Nedd4) in a Xenopus oocyte expression system. Deletion experiments showed that the C-terminal region of the KCNQ3 subunit is required for the Nedd4-2-mediated regulation of the heteromeric channels. Glutathione S-transferase fusion pulldowns and co-immunoprecipitations demonstrated a direct interaction between KCNQ2/3 and Nedd4-2. Furthermore, Nedd4-2 could ubiquitinate KCNQ2/3 in transfected cells. Taken together, these data suggest that Nedd4-2 is potentially an important regulator of M-current activity in the nervous system.

Original languageEnglish
Pages (from-to)12135-12142
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number16
DOIs
Publication statusPublished - 20 Apr 2007
Externally publishedYes

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    Ekberg, J., Schuetz, F., Boase, N. A., Conroy, S. J., Manning, J., Kumar, S., Poronnik, P., & Adams, D. J. (2007). Regulation of the voltage-gated K+ channels KCNQ2/3 and KCNQ3/5 by ubiquitination: Novel role for Nedd4-2. Journal of Biological Chemistry, 282(16), 12135-12142. https://doi.org/10.1074/jbc.M609385200