Title

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

RIS ID

105693

Publication Details

Ekberg, J., Schuetz, F., Boase, N. A., Conroy, S., 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.

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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Link to publisher version (DOI)

http://dx.doi.org/10.1074/jbc.M609385200