Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 9, Pages 2859-2864Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1414002112
Keywords
zebrafish; touch response; voltage-gated sodium channel; ubiquitin; escape
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Funding
- Takeda Science Foundation
- Inamori Foundation
- Collaborative Research Grant from the National Institute of Genetics
- National Institute of Neurological Disorders and Stroke [R01 NS054731]
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Grants-in-Aid for Scientific Research [23241063, 25830020, 15K14373] Funding Source: KAKEN
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Following their synthesis in the endoplasmic reticulum (ER), voltage-gated sodium channels (Na-V) are transported to the membranes of excitable cells, where they often cluster, such as at the axon initial segment of neurons. Although the mechanisms by which Na-V channels form and maintain clusters have been extensively examined, the processes that govern their transport and degradation have received less attention. Our entry into the study of these processes began with the isolation of a new allele of the zebrafish mutant alligator, which we found to be caused by mutations in the gene encoding really interesting new gene (RING) finger protein 121 (RNF121), an E3-ubiquitin ligase present in the ER and cis-Golgi compartments. Here we demonstrate that RNF121 facilitates two opposing fates of Na-V channels: (i) ubiquitin-mediated proteasome degradation and (ii) membrane localization when coexpressed with auxiliary Na-V beta subunits. Collectively, these results indicate that RNF121 participates in the quality control of NaV channels during their synthesis and subsequent transport to the membrane.
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