The human ether-a-go-go-related gene (hERG) encodes the pore-forming α-subunit 
of the rapidly activating delayed rectifier K(+) channel in the heart, which 
plays a critical role in cardiac action potential repolarization. Dysfunction of 
IKr causes long QT syndrome, a cardiac electrical disorder that predisposes 
affected individuals to fatal arrhythmias and sudden death. The homeostasis of 
hERG channels in the plasma membrane depends on a balance between protein 
synthesis and degradation. Our recent data indicate that hERG channels undergo 
enhanced endocytic degradation under low potassium (hypokalemia) conditions. The 
GTPase Rab4 is known to mediate rapid recycling of various internalized proteins 
to the plasma membrane. In the present study, we investigated the effect of Rab4 
on the expression level of hERG channels. Our data revealed that overexpression 
of Rab4 decreases the expression level of hERG in the plasma membrane. Rab4 does 
not affect the expression level of the Kv1.5 or EAG K(+) channels. 
Mechanistically, our data demonstrate that overexpression of Rab4 increases the 
expression level of endogenous Nedd4-2, a ubiquitin ligase that targets hERG but 
not Kv1.5 or EAG channels for ubiquitination and degradation. Nedd4-2 undergoes 
self- ubiquitination and degradation. Rab4 interferes with Nedd4-2 degradation, 
resulting in an increased expression level of Nedd4-2, which targets hERG. In 
summary, the present study demonstrates a novel pathway for hERG regulation; 
Rab4 decreases the hERG density at the plasma membrane by increasing the 
endogenous Nedd4-2 expression.