Copyright © 2007, European Society of Cardiology
The KCNQ1 potassium channel is down-regulated by ubiquitylating enzymes of the Nedd4/Nedd4-like family
aDepartment of Pharmacology and Toxicology, University of Lausanne, Switzerland
bInserm, UMR 533, l'institut du thorax, Université de Nantes, Nantes, France
cThe Danish National Research Foundation Center for Cardiac Arrhythmia, University of Copenhagen, Denmark
dService of Cardiology, CHUV, Lausanne, Switzerland
* Corresponding author. Department of Pharmacology and Toxicology and Service of Cardiology, University of Lausanne Bugnon, 27, 1005 Lausanne, Switzerland. Tel.: +41 21 6925364; fax: +41 21 6935355. Email address: Hugues.Abriel{at}unil.ch
Objective: The voltage-gated KCNQ1 potassium channel regulates key physiological functions in a number of tissues. In the heart, KCNQ1 
-subunits assemble with KCNE1 β-subunits forming a channel complex constituting the delayed rectifier current IKs. In epithelia, KCNQ1 channels participate in controlling body electrolyte homeostasis. Several regulatory mechanisms of the KCNQ1 channel complexes have been reported, including protein kinase A (PKA)-phosphorylation and β-subunit interactions. However, the mechanisms controlling the membrane density of KCNQ1 channels have attracted less attention.
Methods and results: Here we demonstrate that KCNQ1 proteins expressed in HEK293 cells are down-regulated by Nedd4/Nedd4-like ubiquitin-protein ligases. KCNQ1 and KCNQ1/KCNE1 currents were reduced upon co-expression of Nedd4-2, the isoform among the nine members of the Nedd4/Nedd4-like family displaying the highest expression level in human heart. In vivo expression of a catalytically inactive form of Nedd4-2, able to antagonize endogenous Nedd4-2 in guinea-pig cardiomyocytes, increased IKs significantly, but did not modify IK1. Concomitant with the reduction in current induced by Nedd4-2, an increased ubiquitylation as well as a decreased total level of KCNQ1 proteins were observed in HEK293 cells. Pull-down and co-immunoprecipitation experiments showed that Nedd4-2 interacts with the C-terminal part of KCNQ1. The Nedd4/Nedd4-like-mediated regulation of the KCNQ1 channel complexes is strictly dependent on a PY motif located in the distal part of the C-terminal domain. When this motif was mutated, the current and ubiquitylation levels were unaffected by Nedd4-2, and Nedd4-2 proteins were neither pulled-down nor co-immunoprecipitated.
Conclusions: These results suggest that KCNQ1 internalization and stability is physiologically regulated by its Nedd4/Nedd4-like-dependent ubiquitylation. This mechanism may thereby be important in regulating the surface density of the KCNQ1 channels in cardiomyocytes and other cell types.
KEYWORDS KCNQ1; KCNE1; WWP2; qPCR; Ubiquitin; Nedd4
Time for primary review 30 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  X. Xu, V. A. Kanda, E. Choi, G. Panaghie, T. K. Roepke, S. A. Gaeta, D. J. Christini, D. J. Lerner, and G. W. Abbott MinK-dependent internalization of the IKs potassium channel Cardiovasc Res, June 1, 2009; 82(3): 430 - 438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C.G. van Ginneken MinK: a double-hearted partner in cardiac repolarization Cardiovasc Res, June 1, 2009; 82(3): 390 - 391. [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Edinger, J. Lebowitz, H. Li, R. Alzamora, H. Wang, J. P. Johnson, and K. R. Hallows Functional Regulation of the Epithelial Na+ Channel by I{kappa}B Kinase-{beta} Occurs via Phosphorylation of the Ubiquitin Ligase Nedd4-2 J. Biol. Chem., January 2, 2009; 284(1): 150 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Saslowsky, N. Tanaka, K. P. Reddy, and W. I. Lencer Ceramide activates JNK to inhibit a cAMP-gated K+ conductance and Cl- secretion in intestinal epithelia FASEB J, January 1, 2009; 23(1): 259 - 270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. He, D. H. Hryciw, M. L. Carroll, S. A. Myers, A. K. Whitbread, S. Kumar, P. Poronnik, and J. D. Hooper The Ubiquitin-Protein Ligase Nedd4-2 Differentially Interacts with and Regulates Members of the Tweety Family of Chloride Ion Channels J. Biol. Chem., August 29, 2008; 283(35): 24000 - 24010. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Heitzmann and R. Warth Physiology and Pathophysiology of Potassium Channels in Gastrointestinal Epithelia Physiol Rev, July 1, 2008; 88(3): 1119 - 1182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Haitin and B. Attali The C-terminus of Kv7 channels: a multifunctional module J. Physiol., April 1, 2008; 586(7): 1803 - 1810. [Abstract] [Full Text] [PDF]
|
|