The cardiac electrical disorder long QT syndrome (LQTS) pre-disposes affected 
individuals to ventricular arrhythmias and sudden death. Dysfunction of the 
human ether-a-go-go-related gene (hERG)-encoded rapidly activating delayed 
rectifier K(+) channel (IKr) is a major cause of LQTS. The expression of hERG 
channels is controlled by anterograde trafficking of newly synthesized channels 
to and retrograde degradation of existing channels from the plasma membrane. We 
have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural 
precursor cell expressed developmentally down-regulated protein 4-2) targets the 
PY motif of hERG channels to initiate channel degradation. Although both 
immature and mature hERG channels contain the PY motif, Nedd4-2 selectively 
mediates the degradation of mature hERG channels. In the present study, we 
demonstrate that Nedd4-2 is directed to specific cellular compartments by the 
Nedd4 family interacting proteins, Nedd4 family-interacting protein 1 (Ndfip1) 
and Ndfip2. Ndfip1 is primarily localized in the Golgi apparatus where it 
recruits Nedd4-2 to mediate the degradation of mature hERG proteins during 
channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to 
the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies 
(MVBs), which may impair MVB function and impede the degradation of mature hERG 
proteins mediated by Nedd4-2. These findings extend our understanding of hERG 
channel regulation and provide information which may be useful for the rescue of 
impaired hERG function in LQTS.