Regulation of the Voltage-gated K⁺ Channels KCNQ2/3 and KCNQ3/5 by Ubiquitination: NOVEL ROLE FOR Nedd4-2

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 re...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-04, Vol.282 (16), p.12135-12142
Main Authors: Ekberg, Jenny, Schuetz, Friderike, Boase, Natasha A, Conroy, Sarah-Jane, Manning, Jantina, Kumar, Sharad, Poronnik, Philip, Adams, David J
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Animals
Down-Regulation
Endosomal Sorting Complexes Required for Transport
Gene Expression Regulation
Humans
KCNQ Potassium Channels - physiology
KCNQ2 Potassium Channel - physiology
KCNQ3 Potassium Channel - physiology
Membrane Potentials
Nedd4 Ubiquitin Protein Ligases
Oocytes - metabolism
Protein Binding
Rats
Ubiquitin - chemistry
Ubiquitin-Protein Ligases - physiology
Xenopus laevis
Xenopus Proteins
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M609385200