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

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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

Fingerprint

KCNQ3 Potassium Channel
KCNQ2 Potassium Channel
Muscarine
Ubiquitination
Ion Channels
Membranes
Membrane Transport Proteins
Neurology
Ligases
Ubiquitin
Xenopus
Glutathione Transferase
Immunoprecipitation
Membrane Potentials
Nervous System
Neurons
Oocytes
Fusion reactions
Experiments

Cite this

Ekberg, J., Schuetz, F., Boase, N. A., Conroy, S. J., Manning, J., Kumar, S., ... 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
Ekberg, Jenny ; Schuetz, Friderike ; Boase, Natasha A. ; Conroy, Sarah Jane ; Manning, Jantina ; Kumar, Sharad ; Poronnik, Philip ; Adams, David J. / Regulation of the voltage-gated K+ channels KCNQ2/3 and KCNQ3/5 by ubiquitination : Novel role for Nedd4-2. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 16. pp. 12135-12142.
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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.",
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Ekberg, J, Schuetz, F, Boase, NA, Conroy, SJ, Manning, J, Kumar, S, Poronnik, P & Adams, DJ 2007, 'Regulation of the voltage-gated K+ channels KCNQ2/3 and KCNQ3/5 by ubiquitination: Novel role for Nedd4-2' Journal of Biological Chemistry, vol. 282, no. 16, pp. 12135-12142. https://doi.org/10.1074/jbc.M609385200

Regulation of the voltage-gated K+ channels KCNQ2/3 and KCNQ3/5 by ubiquitination : Novel role for Nedd4-2. / Ekberg, Jenny; Schuetz, Friderike; Boase, Natasha A.; Conroy, Sarah Jane; Manning, Jantina; Kumar, Sharad; Poronnik, Philip; Adams, David J.

In: Journal of Biological Chemistry, Vol. 282, No. 16, 20.04.2007, p. 12135-12142.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Regulation of the voltage-gated K+ channels KCNQ2/3 and KCNQ3/5 by ubiquitination

T2 - Novel role for Nedd4-2

AU - Ekberg, Jenny

AU - Schuetz, Friderike

AU - Boase, Natasha A.

AU - Conroy, Sarah Jane

AU - Manning, Jantina

AU - Kumar, Sharad

AU - Poronnik, Philip

AU - Adams, David J.

PY - 2007/4/20

Y1 - 2007/4/20

N2 - 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.

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