Regulation of the cardiac voltage‐gated Na+ channel (H1) by the ubiquitin‐protein ligase Nedd4

FEBS Letters

Kamynina, Elena¹  Staub, Olivier¹  Horisberger, Jean-Daniel¹  Abriel, Hugues¹ 

[1] Institute of Pharmacology and Toxicology, University of Lausanne, CH-1005 Lausanne, Switzerland

关键词: Voltage-gated Na+ channel;    PY motif;    WW domain;    Nedd4;    Ubiquitination;    Protein–protein interaction;   

DOI  :  10.1016/S0014-5793(00)01098-X

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The cardiac voltage-gated Na⁺ channel H1, involved in the generation of cardiac action potential, contains a C-terminal PY motif (xPPxY). Since PY motifs are known ligands to WW domains, we investigated their role for H1 regulation and the possible involvement of the WW domain containing ubiquitin-protein ligase Nedd4, taking advantage of the Xenopus oocyte system. Mutation of the PY motif leads to higher peak currents when compared to wild-type channel. Moreover, co-expression of Nedd4 reduced the peak currents, whereas an enzymatically inactive Nedd4 mutant increased them, likely by competing with endogenous Nedd4. The effect of Nedd4 was not observed in the PY motif mutated channel or in the skeletal muscle voltage-gated Na⁺ channel, which lacks a PY motif. We conclude that H1 may be regulated by Nedd4 depending on WW–PY interaction, and on an active ubiquitination site.

【 授权许可】

Unknown