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Rab4 GTPase regulates cell surface expression of hERG channels through Nedd4–2

The human ether‐a‐go‐go‐related gene (hERG) encodes the pore‐forming subunits of the cardiac rapidly activating delayed rectifier K+ channel (IKr) which is important for cardiac repolarization. Dysfunction of IKr causes long QT syndrome (LQTS), a cardiac electrical disorder which can lead to cardiac arrhythmias and sudden death. Currently, trafficking mechanisms of the hERG channel are poorly understood. We investigated the effects of Rab4 GTPase on the function and expression of hERG channels using Western blot, patch clamp and immunofluorescence staining. Our data revealed that Rab4 selectively decreased the hERG expression on the plasma membrane. Mechanistically, Rab4 did not directly target the hERG protein. Instead, it increased the expression of ubiquitin ligase Nedd4–2, which mediates hERG ubiquitination and degradation. Mutations that disrupt the Nedd4–2 targeting site in hERG completely abolished the effect of Rab4. Our data further revealed that Rab4 inhibited Nedd4–2 self ubiquitination, leading to a decreased degradation rate of Nedd4–2. We conclude that Rab4 regulates the cell surface expression of hERG channels through Nedd4–2.