The KCNQ1 potassium channel is down-regulated by ubiquitylating enzymes of the Nedd4/Nedd4-like family.

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Serval ID
serval:BIB_70DCDFB82A21
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The KCNQ1 potassium channel is down-regulated by ubiquitylating enzymes of the Nedd4/Nedd4-like family.
Journal
Cardiovascular Research
Author(s)
Jespersen T., Membrez M., Nicolas C.S., Pitard B., Staub O., Olesen S.P., Baró I., Abriel H.
ISSN
0008-6363
Publication state
Published
Issued date
2007
Peer-reviewed
Oui
Volume
74
Number
1
Pages
64-74
Language
english
Notes
Journal Article Research Support, Non-U.S. Gov't --- Old month value: Apr 1
Abstract
OBJECTIVE: The voltage-gated KCNQ1 potassium channel regulates key physiological functions in a number of tissues. In the heart, KCNQ1 alpha-subunits assemble with KCNE1 beta-subunits forming a channel complex constituting the delayed rectifier current I(Ks). 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 beta-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 I(Ks) significantly, but did not modify I(K1). 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
Animals, Cell Line, Down-Regulation, Gene Expression, Guinea Pigs, Humans, KCNQ1 Potassium Channel, Myocytes, Cardiac, Patch-Clamp Techniques, Potassium Channels, Voltage-Gated, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Transfection, Ubiquitin, Ubiquitin-Protein Ligases
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 10:56
Last modification date
25/09/2019 6:09
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