title: Regulation of the human ether-a-go-go-related gene (hERG) channel by Rab4 protein through neural precursor cell-expressed developmentally down-regulated protein 4-2 (Nedd4-2).
abstract: 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.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Cui
authors.forename: Shetuan
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D000072237:ERG1 Potassium Channel; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D000075702:Nedd4 Ubiquitin Protein Ligases; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D020695:rab4 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000072237:ERG1 Potassium Channel; D056827:Endosomal Sorting Complexes Required for Transport; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D049452:Green Fluorescent Proteins; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618484:Nedd4 protein, rat; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases; D020695:rab4 GTP-Binding Proteins
keywords: Cardiovascular; Cell Biology; Gene Expression; HERG; Patch Clamp; Potassium Channels; Protein Degradation; Rab; Trafficking; Ubiquitin Ligase