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

Ekberg, Jenny, Schuetz, Frederike, Boase, Natasha A., Conroy, Sarah-Jane, Manning, Jantina, Kumar, Sharad, Poronnik, Philip and Adams, David 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. doi:10.1074/jbc.M609385200

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Author Ekberg, Jenny
Schuetz, Frederike
Boase, Natasha A.
Conroy, Sarah-Jane
Manning, Jantina
Kumar, Sharad
Poronnik, Philip
Adams, David J.
Title Regulation of the voltage-gated K+ channels KCNQ2/3 and KCNQ3/5 by ubiquitination - Novel role for Nedd4-2
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2007
Sub-type Article (original research)
DOI 10.1074/jbc.M609385200
Open Access Status File (Publisher version)
Volume 282
Issue 16
Start page 12135
End page 12142
Total pages 8
Editor Tabor, H
Place of publication United States
Publisher American Society for Biochemistry and Molecular Biology, Inc.
Collection year 2008
Language eng
Subject 320502 Basic Pharmacology
730104 Nervous system and disorders
320700 Neurosciences
320307 Medical Biochemistry - Other
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.
Keyword Biochemistry & Molecular Biology
Q-Index Code C1
Q-Index Status Confirmed Code

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Created: Wed, 23 Apr 2008, 17:43:21 EST by Timothy Hazelton on behalf of School of Biomedical Sciences