ArticleThe Journal of biological chemistry2013
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).
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 33 citations in OpenAlex.
- Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome.Cell discovery · 2025Review
- Article
- Pharmacological suppression of Nedd4-2 rescues the reduction of Kv11.1 channels in pathological cardiac hypertrophy.Frontiers in pharmacology · 2022Article
- Agonist-activated glucagon receptors are deubiquitinated at early endosomes by two distinct deubiquitinases to facilitate Rab4a-dependent recycling.The Journal of biological chemistry · 2020Article
- Review
- AMPK phosphorylation of the βAmerican journal of physiology. Renal physiology · 2019Article
- PLPP/CIN-mediated NEDD4-2 S448 dephosphorylation regulates neuronal excitability via GluA1 ubiquitination.Cell death & disease · 2019Article
- Rab GTPases regulate the trafficking of channels and transporters - a focus on cystic fibrosis.Small GTPases · 2018Review
- Proteasome dysfunction in cardiomyopathies.The Journal of physiology · 2017Review
- Epilepsy-associated gene Nedd4-2 mediates neuronal activity and seizure susceptibility through AMPA receptors.PLoS genetics · 2017Article
- Rab25 influences functional Cav1.2 channel surface expression in arterial smooth muscle cells.American journal of physiology. Cell physiology · 2016Article
- Rab11-dependent Recycling of the Human Ether-a-go-go-related Gene (hERG) Channel.The Journal of biological chemistry · 2015Article
- Review
- Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects.Acta pharmacologica Sinica · 2014Review
- Rab proteins and the compartmentalization of the endosomal system.Cold Spring Harbor perspectives in biology · 2014Review
- Article
- Up-regulation of hERG K⁺ channels by B-RAF.PloS one · 2014Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.