Guo J, Wang T, Li X, Shallow H, Yang T, Li W, Xu J, Fridman MD, Yang X, Zhang S

The human ether-a-go-go-related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel (I(Kr)) which plays an important role in cardiac repolarization. A reduction or increase in hERG current can cause long or short QT syndrome, respectively, leading to fatal cardiac arrhythmias. The channel density in the plasma membrane is ...

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a key determinant of the whole cell current amplitude. To gain insight into the molecular mechanisms for the regulation of hERG density at the plasma membrane, we used whole-cell voltage clamp, Western blot, and immunocytochemistry methods to investigated the effects of an integral membrane protein, caveolin 3 (Cav3) on hERG expression levels. Our data demonstrate that Cav3, hERG and ubiquitin-ligase Nedd4-2 interact with each other and form a complex. Expression of Cav3 thus enhances hERG-Nedd4-2 interaction, leading to an increased ubiquitination and degradation of mature hERG channels expressed in the plasma membrane. Disrupting Nedd4-2 interaction with hERG by mutations eliminates Cav3 effects on hERG channels. Knockdown of endogenous Cav3 or Nedd4-2 in cultured neonatal rat ventricular myocytes via siRNA led to an increase in native I(Kr). Our data indicate that hERG expression in the plasma membrane is regulated by Cav3 via Nedd4-2. These findings extend our understanding of the regulation of hERG channels and cardiac electrophysiology.

Date: Aug. 09, 2012

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